DESCRIPTION

METHODS AND COMPOSITIONS INVOLVING A FLU VACCINE

BACKGROUND OF THE INVENTION

[0001] This application claims priority to U.S. Provisional Patent Applications Serial No. 61/730,930 filed on November 28, 2012, incorporated herein by reference in its entirety.

1. Field of the Invention

[0002] The present invention relates generally to the field of medicine. More particularly, it concerns virology and immunology, including, but not limited to methods and compositions for vaccinating a subject against influenza virus using a dendritic cell targeting agent and at least one influenza antigen such as hemagglutinin (HA) or nucleoprotein (NP).

2. Description of Related Art

[0003] It is estimated that every year a quarter to a half million people die from influenza infection and that three to five million are infected. Flu vaccines are available, however, due to the mutation rates in influenza viruses, their efficacy varies from year to year. New vaccines for flu are needed especially because there is a risk of a global pandemic of influenza A infection.

SUMMARY OF THE INVENTION

[0004] Methods and compositions are provided that can be used to vaccinate against and treat infection from influenza virus and flu. Specifically contemplated are vaccine compositions and methods of administering these compositions to patients. Embodiments are focused on compositions containing at least one influenza virus antigen (also referred to as influenza antigen) that is attached, fused, coupled to, or conjugated to a dendritic cell targeting agent such that the influenza antigen is provided to the dendritic cell via the targeting agent such as through receptor-mediated endocytosis. In certain embodiments, compositions contain one or more adjuvants. In particular embodiments, there are methods of protecting a subject against infection from one or more of influenzavirus A, influenzavirus B, or influenzavirus C.

[0005] Methods are provided for of inducing an immune response to at least one influenza antigen in a patient comprising administering to the patient an effective amount of a composition comprising a dendritic cell targeting complex comprising a dendritic cell antibody, or targeting fragment thereof, attached to the at least one influenza antigen.

[0006] Additional methods concern vaccinating a subject against flu comprising administering to the subject a pharmaceutically acceptable vaccine composition comprising a) at least at first CD40 antibody, or binding fragment thereof, attached to at least a first hemagglutinin (HA) antigen; and b) Flagellin.

[0007] In particular embodiments, the dendritic cell targeting agent is an antibody that recognizes a receptor on a dendritic cell. In some cases, the antibody specifically recognizes LOX-1, CD40, DCIR, CD1A, DC-SIGN, DC-SIGN/L, CLEC-6, DC-ASGPR, LANGERIN, or DECTIN-1. It is also contemplated that the dendritic cell targeting agent may be a compound that binds to a dendritic cell receptor and that promotes receptor-mediated endocytosis. The antibody may be all or part of an antibody, such as an antibody fragment, or it may be an antibody that has been modified. In certain embodiments, the antibody has a variable region or 1, 2, 3, 4, 5, and/or 6 CDRs from the light and/or heavy chains of an antibody that recognizes LOX-1, CD40, DCIR, CD1A, DC-SIGN, DC-SIGN/L, CLEC-6, DC-ASGPR, LANGERIN, or DECTIN-1. In further embodiments, the antibody is a monoclonal antibody. A monoclonal antibody may be from a mouse, rat, rabbit, human or other mammal. In cases where the antibody is not a human antibody, the antibody may be humanized. An antibody fragment refers to a portion of the antibody that allows the fragment to target a dendritic cell. Therefore, the antibody fragment minimally contains a dendritic cell binding domain or region or amino acid sequence.

[0008] In certain embodiments, an antibody or antibody fragment has a sequence that is 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identical (and any range derivable therein) to any of the antibody sequences provided in SEQ ID NOs: 123, 125, 127, 129, 131 , 133, 135, 137, 139, and 141. Moreover, an antibody may have one or more CDRs from these SEQ ID NOs. In further embodiments, it has, has at least or hast at most 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more regions (or any range derivable therein) that have at least or at most 5, 6, 7, 8, 9, 10 or more contiguous amino acids (or any range derivable therein) from SEQ ID NOs: 123, 125, 127, 129, 131, 133, 135, 137, 139, and 141. [0009] Methods and compositions concern antigens from an influenza virus. In certain embodiments, the influenza antigen is hemagglutinin (HA) or nucleoprotein (NP). In certain embodiments, at least one HA antigen and at least one NP antigen are included in a composition. It is contemplated that methods and composition may involve 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more influenza antigens (or any range derivable therein). The antigens may be the same and/or different with respect to the identity of the antigen, but also with respect to the specific amino acid sequence of the antigen. In some embodiments, the same antigen is used in a composition but from multiple serotypes. It is contemplated that an antigen may be from an influenza virus from the genera influenzavirus A, influenzavirus B, or influenzavirus C. In certain embodiments, a composition or method involves influenza antigens from one, two or all three of influenza viruses that are influenzavirus A, influenzavirus B, or influenzavirus C. In some embodiments, a method or composition involves at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 HA antigens from influenzavirus A (or any range derivable therein). Additionally or alternatively, in some embodiments a method or composition involves at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 HA antigens from influenzavirus B (or any range derivable therein). In particular embodiments, a composition or method concerns at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 NP antigens from influenzavirus A (or any range derivable therein) and/or from influenzavirus B (or any range derivable therein).

[0010] In some embodiments, compositions or methods may involve influenza antigens from, from at least, or from at most 1 , 2, 4, 5, 6, 7, or 8 different influenza serotypes (or any range derivable therein). In some embodiments, the influenza antigen may be from H1N1 , H2N2, H3N2, H5N1 , H7N7, H1N2, H9N2, H7N2, H7N3 or H10N7. For instance, there may be 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more NP and/or HA antigens by virtue of having antigens from different serotypes and/or genera of influenzaviruses. In specific embodiments, the NP influenza antigen is NP-1 , NP-ls, or NP-5. In particular cases, the NP influenza antigen is, is at least, or is at most 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99, or 100% identical (or any range derivable therein) to any of SEQ ID NOs: 106, 107, 108, 109 and 110. In specific embodiments, the HA influenza antigen is HAl-l s, HA3- lk, HAl-lc, HAb-1, or HA 1 -headless. In particular cases, the HA influenza antigen is, is at least, or is at most 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99, or 100% identical (or any range derivable therein) to any of SEQ ID NOs: 96, 97, 98, 99, and 100.

[0011] In some embodiments, methods and compositions include multiple dendritic cell targeting complexes. In certain cases, the multiple dendritic cell targeting complexes comprise the same influenza antigen, wherein the influenza antigen is from different influenza serotypes. In particular embodiments, multiple dendritic cell targeting complexes comprise the same influenza antigen, wherein the polypeptide sequences of the antigen differ by, by at least or up to 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10% of the antigen's amino acids (and any range derivable therein).

[0012] Embodiments involve methods and composition in which an influenza antigen is from influenzavirus A This means the amino acid sequence of the influenza antigen corresponds to the amino acid sequence of that influenza antigen in an influenza virus from the genera influenzavirus A. Other embodiments concern methods and compositions in which an influenza antigen is from influenzavirus B. In some cases, a composition comprises at least one influenza antigen from influenzavirus A and at least one influenza antigen from influenzavirus B. In certain embodiments, the vaccine composition is trivalent. It can comprise two influenza antigens from influenzavirus A and an influenza antigen from influenzavirus B, or vice versa. Furthermore, compositions and methods may involve a "universal" antigen meaning it provides protection against more than one serotype of influenza virus. In some cases the universal antigen provides protection against at least or at most 3, 4, 5, 6, 7, 8, 9, 10 or more serotypes.

[0013] In certain embodiments, a CD40 antibody, or binding fragment thereof, is fused to the first HA antigen. In additional embodiments, methods and compositions comprise a CD40 antibody, or binding fragment thereof, attached to at least a second HA antigen, wherein the first and second HA antigens are not identical. In further embodiments, the first and second HA antigens differ in amino acid sequence. In other embodiments, a composition comprises a CD40 antibody, or binding fragment thereof, attached to at least a third HA antigen, wherein the first, second, and third HA antigens are not identical. [0014] Methods and compositions may involve multiple dendritic cell targeting complexes or different influenza antigens, where each different influenza antigen is separately attached to a dendritic cell antibody, or a targeting fragment thereof.

[0015] In some cases, a dendritic cell antibody, or fragment thereof, is attached to the influenza antigen using a linker. In certain embodiments, the linker is a peptide linker. In a particular embodiment, the PL comprises an alanine and a serine. In another embodiment, the PL further comprises a flexible linker. In some cases, flexible linker sequences are derived from Scaffoldins and related proteins. In one embodiment, the flexible linker is QTPTNTISVTPTNNSTPTNNSNPKPNP (SEQ ID NO: 142). In another embodiment, the flexible linker is QTPTNTISVTPTNNSTPTNTSTPKPNP (SEQ ID NO: 142). In certain embodiments, two PL comprising an alanine and a serine are separated by the flexible linker. In another embodiment, the flexible linker comprises one or more glycosylation sites that provide increased flexibility between the antibody and the antigen, decreased proteolysis at the linker and increased secretion. In additional embodiments the linker is Flex-vl (SEQ ID NO:93), Flexx-vl (SEQ ID NO:94), or Flexx-v2 (SEQ ID NO:95).

[0016] As demonstrated in the Examples section below, engineered recombinant antibody-antigen fusion proteins are efficient vaccines in vivo.

[0017] Expression vectors may be constructed with diverse protein coding sequence e.g., fused in-frame to the H chain coding sequence. For example, influenza antigens such as HA antigen or NP antigen may be expressed subsequently as Ab.Ag, which can have utility derived from using the dendritic cell antibody sequence to bring the antigen directly to the surface of the antigen presenting cell bearing the dendritic cell antigen recognized by the antibody. This permits internalization of e.g., antigen and ensuing initiation of therapeutic or protective action (e.g., via initiation of a potent immune response).

[0018] In some cases, particular amino acid sequences corresponding to dendritic cell monoclonal antibodies that are desirable components (in the context of e.g., humanized recombinant antibodies) of therapeutic or protective products. The following are such sequences in the context of chimeric mouse V region (underlined) human C region recombinant antibodies. These mouse V regions can be readily humanized, i.e., the antigen combining regions grafted onto human V region framework sequences, by anyone well practiced in this art. Furthermore, the sequences can also be expressed in the context of fusion proteins that preserve antibody functionality, but add e.g., antigen for desired therapeutic applications.

[0019] Vaccine compositions may also contain one or more adjuvants. A composition may contain at least or at most 1 , 2, 3 ,4 , 5 or more different adjuvants (or any range derivable therein). The adjuvants may be attached or conjugated directly or indirectly to one or more of the vaccine components, such as an antigen or antibody. In other embodiments the adjuvants may be provided or administered separately from the vaccine composition. In certain embodiments the adjuvant is poly ICLC, CpG, LPS, Immunoquid, PLA, GLA or cytokine adjuvants such as IFNa. In other embodiments the adjuvant may be a toll-like receptor agonist (TLR). Examples of TLR agonists that may be used comprise TLR1 agonist, TLR2 agonist, TLR3 agonist, TLR4 agonist, TLR5 agonist, TLR6 agonist, TLR7 agonist, TLR8 agonist or TLR9 agonist. In certain embodiments, a vaccine composition specifically does not contain PLA as an adjuvant. In other embodiments, the adjuvant is adjuvant is a TLR agonist, Flagellin, IL-21, IL-2, IL-9, interferon, IL-10, or other cytokine.

[0020] In specific embodiments, the adjuvant is attached to the dendritic cell targeting complex or to a component of the dendritic cell targeting complex. It may be attached to the dendritic cell antibody, to one or more influenza antigens or both. Alternatively, in certain embodiments, the adjuvant is included in a vaccine composition but is not covalently attached to an antibody or antigen. In some embodiments, the adjuvant is conjugated to the dendritic cell targeting complex or to a component of the dendritic cell targeting complex. In particular cases, an adjuvant is fused to the dendritic cell antibody, or targeting fragment thereof, and/or to the at least one influenza antigen.

[0021] Alternatively, the dendritic cell antibody or fragment is bound or fused to one half of a binding polypeptide pair. In some embodiments the binding polypeptide pair is Cohesin/Dockerin pair and the influenza antigen is bound or fused to the complementary half of the Cohesin/Dockerin pair to form said antibody-antigen complex (Ab:Ag). [0022] Non limiting examples of sources for the cohesin-dockerin binding pair include Clostridium thermocellum, Clostridium josui, Clostridium cellulolyticum and Bacteroides cellulosolvens and combinations thereof.

[0023] In one embodiment, the antibody-antigen complex (Ab:Ag) comprises the following formula Ab.Doc:Coh.Ag;

Ab.Coh:Doc.Ag;

Ab.(Coh)x:(Doc.Ag)x;

Ab.(Doc)x:(Coh.Ag)x; Ab.(Coh.Doc)x:(Doc.Ag')(Coh.Ag ² ); or

Ab.iCoh Doc^^Doc.Ag'XCoh.Ag ² )^; wherein Ab is a dendritic cell antibody or a fragment thereof; wherein Ag is an influenza antigen (Ag ¹ and Ag ² being two distinct influenza antigens); wherein Doc is Dockerin; wherein Coh is Cohesin and wherein x is an integer from 1 to 10, or any range derivable therein. In some embodiments, the dendritic cell antibody is attached to at least one influenza antigen through binding polypeptides.

[0024] It is contemplated that at least one influenza antigen elicits at least one of a humoral and/or a cellular immune response in a host, preferably a human patient. [0025] In certain methods, a vaccine composition is administered multiple times. It may be administered 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times (or any range derivable therein). After the first administration, subsequent administrations may be considered boosters. In other circumstances a vaccine composition may be administered seasonally meaning it is given when the risk of influenza infection is higher than at other times of the year. In certain cases, the vaccine is optionally administered annually. In some cases, it is administered to a subject who is at least 50, 55, 60, 65 years or older. In other cases, it is administered to a child who is less than 2 years old, such as a child that is less than 1 day, 1 week, 1 month or 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23 or 24 months old or younger. [0026] In certain embodiments, a subject exhibits one or more symptoms of a flu infection. In other cases, the subject is at risk of death from an influenza infection. In some embodiments, the subject has previously received a flu vaccine. In further embodiments, the subject is suspected of having been exposed to influenza or is at risk for influenza infection.

[0027] Methods also include preparing or manufacturing the composition. Additional embodiments involve measuring antibodies against at least one influenza antigen in the subject after administering the composition.

[0028] In some embodiments, a vaccine composition is administered orally, intravenously, subcutaneously, intramuscularly, nasally, by injection, by inhalation, and/or using a nebulizer. [0029] The preparation of an influenza vaccine as the active immunogenic ingredient, may be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid prior to infection can also be prepared. The preparation may be emulsified, encapsulated in liposomes. The active immunogenic ingredients are often mixed with carriers which are pharmaceutically acceptable and compatible with the active ingredient.

[0030] The term "pharmaceutically acceptable carrier" refers to a carrier that does not cause an allergic reaction or other untoward effect in subjects to whom it is administered. Suitable pharmaceutically acceptable carriers include, for example, one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, or the like and combinations thereof. In addition, if desired, the vaccine can contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and/or adjuvants which enhance the effectiveness of the vaccine. Examples of adjuvants that may be effective include but are not limited to: aluminum hydroxide, N-acetyl-muramyl-L-threonyl-D-isoglutamine (thr- MDP), N-acetyl-nor-muramyl-L-alanyl-D-isoglutamine, MTP-PE and RIBI, which contains three components extracted from bacteria, monophosphoryl lipid A, trehalose dimycolate and cell wall skeleton (MPL+TDM+CWS) in a 2% squalene/Tween 80 emulsion. Other examples of adjuvants include DDA (dimethyldioctadecylammonium bromide), Freund's complete and incomplete adjuvants and QuilA. In addition, immune modulating substances such as lymphokines (e.g., IFN-[gamma], IL-2 and IL-12) or synthetic IFN-[gamma] inducers such as poly I:C can be used in combination with adjuvants described herein.

[0031] Vaccines may include an effective amount of the antibody-antigen fusion protein (Ab.Ag) or the antibody-antigen complex (Ab:Ag), dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium. Such compositions can also be referred to as inocula. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients also can be incorporated into the compositions. The compositions of the present invention may include classic pharmaceutical preparations. Dispersions also can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. [0032] Administration of vaccines according to the present invention will be via any common route so long as the target tissue is available via that route in order to maximize the delivery of antigen to a site for maximum (or in some cases minimum) immune response. Administration will generally be by orthotopic, intradermal, subcutaneous, intramuscular, intraperitoneal or intravenous injection. Other areas for delivery include: oral, nasal, buccal, rectal, vaginal or topical. Vaccines of the invention are preferably administered parenterally, by injection, for example, either subcutaneously or intramuscularly.

[0033] Vaccines may be administered in a manner compatible with the dosage formulation, and in such amount as will be prophylactically and/or therapeutically effective. The quantity to be administered depends on the subject to be treated, including, e.g., capacity of the subject's immune system to synthesize antibodies, and the degree of protection or treatment desired. Suitable dosage ranges are of the order of several hundred micrograms active ingredient per vaccination with a range from about 0.1 mg to 1000 mg, such as in the range from about 1 mg to 300 mg, or in the range from about 10 mg to 50 mg. Suitable regiments for initial administration and booster shots are also variable but are typified by an initial administration followed by subsequent inoculations or other administrations. Precise amounts of active ingredient required to be administered depend on the judgment of the practitioner and may be peculiar to each subject. It will be apparent to those of skill in the art that the therapeutically effective amount of nucleic acid molecule or fusion polypeptides of this invention will depend, inter alia, upon the administration schedule, the unit dose of antigen administered, whether the antibody-antigen fusion protein (Ab.Ag) or the antibody- antigen complex (Ab:Ag) is administered in combination with other therapeutic agents, the immune status and health of the recipient, and the therapeutic activity of the particular the Ab.Ag or the Ab:Ag. [0034] A vaccine may be given in a single dose schedule or in a multiple dose schedule. A multiple dose schedule is one in which a primary course of vaccination may include, e.g., 1-10 separate doses, followed by other doses given at subsequent time intervals required to maintain and or reinforce the immune response, for example, at 1 -4 months for a second dose, and if needed, a subsequent dose(s) after several months. Periodic boosters at intervals of 1 -5 years, usually 3 years, are desirable to maintain the desired levels of protective immunity. The course of the immunization can be followed by in vitro proliferation assays of peripheral blood lymphocytes (PBLs) co-cultured with ESAT6 or ST- CF, and by measuring the levels of IFN-[gamma] released from the primed lymphocytes. The assays may be performed using conventional labels, such as radionucleotides, enzymes, fluorescent labels and the like. These techniques are known to one skilled in the art and can be found in U.S. Pat. Nos. 3,791 ,932, 4,174,384 and 3,949,064, relevant portions incorporated by reference.

[0035] A vaccine may be provided in one or more "unit doses". Unit dose is defined as containing a predetermined-quantity of the vaccine calculated to produce the desired responses in association with its administration, i.e., the appropriate route and treatment regimen. The quantity to be administered, and the particular route and formulation, are within the skill of those in the clinical arts. The subject to be treated may also be evaluated, in particular, the state of the subject's immune system and the protection desired. A unit dose need not be administered as a single injection but may include continuous infusion over a set period of time. Unit dose of the present invention may conveniently may be described in terms of DNA/kg (or protein/Kg) body weight, with ranges between about 0.05, 0.10, 0.15, 0.20, 0.25, 0.5, 1, 10, 50, 100, 1 ,000 or more mg/DNA or protein/kg body weight are administered. Tikewise the amount of vaccine delivered can vary from about 0.2 to about 8.0 mg/kg body weight. Thus, in particular embodiments, 0.4 mg/kg, 0.5 mg/kg, 0.8 mg/kg, 1.0 mg/kg, 1.5 mg/kg, 2.0 mg/kg, 2.5 mg/kg, 3.0 mg/kg, 4.0 mg/kg, 5.0 mg/kg, 5.5 mg/kg, 6.0 mg/kg, 6.5 mg/kg, 7.0 mg/kg and 7.5 mg/kg of the antibody-producing agent in the vaccine may be delivered to an individual in vivo. The dosage of vaccine to be administered depends to a great extent on the weight and physical condition of the subject being treated as well as the route of administration and the frequency of treatment.

[0036] In another aspect, embodiments relate to a combined influenza vaccine comprising a first influenza vaccine as described above and a second influenza vaccine. It is further contemplated that the influenza antigens provided to the patient in the first and second influenza vaccines may be the same or they may be different. It is also contemplated that the administration of the first and second vaccines can be reversed such that the second vaccine is administered first and the first vaccine is administered second. It additionally is contemplated that the first and second vacccines be administered at the same time. In instances when the first and second vaccines are not administered at the same time it is contemplated that the vaccines may be administered, administered at least, or administered at most 1 , 2, 3, 4, 5, 6, 7,8 ,9, 10, 1 1 , 12, 13 or 14 days apart or 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48 ,49, 50, 51 or 52 weeks apart or 1 , 2, 3, 4, 5, 6, 7,8 ,9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 36, 48, 60, 72, 84 or 96 months apart or 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 years apart. [0037] As discussed above, embodiments concern pharmaceutically acceptable vaccine compositions comprising an adjuvant, a dendritic cell antibody, or targeting fragment thereof, attached to a hemagglutinin or nucleoprotein influenzavirus A or influenzavirus B antigen.

[0038] As used herein, the term "anti-DC receptor antibody" or "dendritic cell antibody" refers to an antibody which specifically binds to a receptor on a dendritic cell. Such an antibody may be a monoclonal antibody (mAb) or have regions from a mAb, which is used for delivering at least one influenza antigen directly to the human dendritic cell for antigen uptake and presentation to antigen-specific T and B cells. Such antibody may also have associated DC activation properties evoked through the binding of the mAb to the DC receptor (e.g., the agonistic anti-CD40 antibody).

[0039] In some embodiments, the mAb is humanized (i.e., converted to a sequence which retains the original key residues crucial for receptor binding, but has variable region framework and constant region sequences that are typically found in human antibodies).

[0040] Non-limiting examples of anti-DC receptor antibodies include, but are not limited to, antibodies which specifically binds to MHC class I, MHC class II, CD1 , CD2, CD3, CD4, CD8, CDl lb, CD14, CD15, CD16, CD19, CD20, CD29, CD31, CD40, CD43, CD44, CD45, CD54, CD56, CD57, CD58, CD83, CD86, CMRF-44, CMRF-56, DCIR, DC- ASGPR, CLEC-6, CD40, BDCA-2, MARCO, DEC-205, mannose receptor, Langerin, DECTIN-1 , B7-1 , B7-2, IFN-γ receptor and IL-2 receptor, ICAM-1 , Fey receptor and ASGPR.

[0041] In certain embodiments, the anti-DC receptor antibody is selected from the group consisting of an anti-Dectin-1 antibody, an anti-DC-ASGPR, an anti-DCIR antibody, an anti-CLEC-6, an anti-CD40 antibody and an anti-Langerin antibody.

[0042] As used herein, the term "vaccine" is intended to mean a composition which can be administered to humans or to animals in order to induce an immune system response; this immune system response can result in a production of antibodies or simply in the activation of certain cells, in particular antigen-presenting cells, T lymphocytes and B lymphocytes. In certain embodiments the vaccine is capable of producing an immune response that leads to the production of neutralizing antibodies in the patient with respect to the antigen provided in the vaccine. The vaccine can be a composition for prophylactic purposes or for therapeutic purposes, or both.

[0043] As used herein, the term "antigen" refers to any antigen that can be used in a vaccine, whether it involves a whole microorganism or a portion thereof, and various types: (e.g., peptide, protein, glycoprotein, polysaccharide, glycolipid, lipopeptide, etc). Thus, the term "antigen" refers to a molecule that can initiate a humoral and/or cellular immune response in a recipient of the antigen. The antigen is usually a molecule that causes a disease for which a vaccination would be advantageous treatment. Within the context of the invention, the antigens are human influenza antigens; the term "antigen" also comprises the polynucleotides, the sequences of which are chosen so as to encode the antigens whose expression by the individuals to which the polynucleotides are administered is desired, in the case of the immunization technique referred to as DNA immunization.

[0044] As used herein, the term "antibodies" refers to immunoglobulins, whether natural or partially or wholly produced artificially, e.g. recombinant. An antibody may be monoclonal or polyclonal. The antibody may, in some cases, be a member of one, or a combination immunoglobulin classes, including: IgG, IgM, IgA, IgD, and IgE.

[0045] As used herein, the term "antibody or fragment thereof," includes whole antibodies or fragments of an antibody, e.g., Fv, Fab, Fab', F(ab')2, Fc, and single chain Fv fragments (ScFv) or any biologically effective fragments of an immunoglobulins that binds specifically to, e.g., LOX-1 or CD40 or DCIR. Antibodies from human origin or humanized antibodies have lowered or no immunogenicity in humans and have a lower number or no immunogenic epitopes compared to non-human antibodies. Antibodies and their fragments will generally be selected to have a reduced level or no antigenicity in humans. A polypeptide that has one or more CDRs from a monoclonal antibody and that may have at least as good as a binding specificity and/or affinity of a monoclonal antibody may be referred to as an "antibody fragment" or a polypeptide comprises an antibody fragment. [0046] Typically, the term "antibody or fragment thereof describes a recombinant antibody system that has been engineered to provide a target specific antibody. The monoclonal antibody made using standard hybridoma techniques, recombinant antibody display, humanized monoclonal antibodies and the like. The antibody can be used to, e.g., target (via one primary recombinant antibody against an internalizing receptor, e.g., a human dendritic cell receptor such as a LOX-1) one or several antigens and/or one adjuvant to dendritic cells. Any embodiment discussed in the context of an antibody may be implemented in the context of an antibody fragment, including a polypeptide comprising one or more CDRs from an antibody. [0047] As used herein, the term "anti-Lectin-like oxidized LDL receptor- 1 (TOX-1) antibody" refers to an antibody which specifically binds to LOX-1. In certain embodiments, a LOX-1 antibody or antibody discussed herein has a KD of at least about or at most about 10 ^"6 , 10 ^"7 ' 10 ^"8 , 10 ^"9 , 10 ^"10 M or any range derivable therein.

[0048] As used herein, the term "monoclonal antibody" refers to an antibody composition having a homogeneous antibody population. The term is not limited regarding the species or source of the antibody, nor is it intended to be limited by the manner in which it is made. The term encompasses whole immunoglobulins as well as fragments such as Fab, F(ab')2, Fv, and other fragments that exhibit immunological binding properties of the parent monoclonal antibody molecule. [0049] As used herein, the term "antigen-binding site" or "binding portion" refers to the part of the immunoglobulin molecule that participates in antigen binding. The antigen binding site is formed by amino acid residues of the N-terminal variable ("V") regions of the heavy ("H") and light ("L") chains. Three highly divergent stretches within the V regions of the heavy and light chains are referred to as "hypervariable regions" which are interposed between more conserved flanking stretches known as "framework regions" (FRs). As used herein, the term "FR" refers to amino acid sequences which are found naturally between and adjacent to hypervariable regions in immunoglobulins. In an antibody molecule, the three hypervariable regions of a light chain and the three hypervariable regions of a heavy chain are disposed relative to each other in three dimensional space to form an antigen-binding surface. The antigen-binding surface is complementary to the three-dimensional surface of a bound antigen, and the three hypervariable regions of each of the heavy and light chains are referred to as "complementarity-determining regions" or "CDRs". [0050] As used herein, the term "humanized" antibody refers to those molecules comprising an antigen-binding site derived from a non-human immunoglobulin have been described, including chimeric antibodies having rodent V regions and their associated CDRs fused to human constant domains, rodent CDRs grafted into a human supporting FR prior to fusion with an appropriate human antibody constant domain, and rodent CDRs supported by recombinantly veneered rodent FRs. These "humanized" molecules are designed to minimize unwanted immunological response toward rodent antihuman antibody molecules, which limits the duration and effectiveness of therapeutic applications of those moieties in human recipients. [0051] The terms "adjuvant" or "immunoadjuvant" may be used interchangeably and refer to a substance that enhances, augments or potentiates the host's immune response to an antigen, e.g., an antigen that is part of a vaccine. Non-limiting examples of some commonly used vaccine adjuvants include insoluble aluminum compounds, calcium phosphate, liposomes, Virosomes™, ISCOMS®, microparticles (e.g., PLG), emulsions (e.g., MF59, Montanides), virus-like particles & viral vectors. PolylCLC (a synthetic complex of carboxymethylcellulose, polyinosinic-polycytidylic acid, and poly-L-lysine double-stranded RNA), which is a TLR3 agonist, is used as an adjuvant in the present invention. It will be understood that other TLR agonists may also be used (e.g. TLR4 agonists, TLR5 agonists, TLR7 agonists, TLR9 agonists), or any combinations or modifications thereof. [0052] As used herein, the term "conjugate" refers to any substance formed from the joining together of two parts. Representative conjugates in accordance with the present invention include those formed by joining together of the antigen with the antibody and/or the adjuvant. The term "conjugation" refers to the process of forming the conjugate and is usually done by physical coupling, e.g. covalent binding, co-ordination covalent, or secondary binding forces, e.g. Van der Waals bonding forces. The process of linking the antigen to the antibody and/or to the adjuvant can also be done via a non-covalent association such as a dockerin-cohesin association (as described in U.S. Patent Publication No. 20100135994, Banchereau et al. relevant portions incorporated herein by reference) or by a direct chemical linkage by forming a peptide or chemical bond. [0053] As used herein, "Dendritic Cells" (DCs) refers to any member of a diverse population of morphologically similar cell types found in lymphoid or non-lymphoid tissues. These cells are characterized by their distinctive morphology, high levels of surface MHC- class II expression (Steinman, et al., Ann. Rev. Immunol. 9:271 (1991 ); incorporated herein by reference for its description of such cells). These cells can be isolated from a number of tissue sources, and conveniently, from peripheral blood, as described herein.

[0054] As used herein the specification, "a" or "an" may mean one or more. As used herein in the claim(s), when used in conjunction with the word "comprising", the words "a" or "an" may mean one or more than one.

[0055] The use of the term "or" in the claims is used to mean "and/or" unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and/or." As used herein "another" may mean at least a second or more.

[0056] Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects.

[0057] Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0059] FIG.l . H1N1 NP antigens.

[0060] FIG.2. Anti-DC receptor-NP vaccines expand NP-specific CD8+ T cells in vitro.

[0061] FIG.3. NHP DC-targeting Influenza NP vaccine studies to date. [0062] FIG.4. Kinetics of HAl -specific T cell response by na ^' ive NHP challenged with live H1N1 - IFNg-ELISPOT analysis.

[0063] FIG.5. Kinetics of NP-specific T cell response by na ^' ive NHP challenged with Live H1N1 - IFNg-ELISPOT analysis.

[0064] FIG.6. NHP CD40-targeting Influenza NP + Poly ICLC vaccine - NP-specific

T cell responses.

[0065] FIG.7. NHP CD40-targeting Influenza NP + Poly ICLC vaccine - delay in HAl -specific T cell response to live virus.

[0066] FIG.8. NHP anti-CD40-targeting Influenza NP + Poly ICLC vaccine - NP- specific serum IgG response responses.

[0067] FIG.9. NHP DC-targeting Influenza NP + Poly ICLC vaccines - NP-specific serum IgG response responses.

[0068] FIG.10. Kinetics of NHP with Poly ICLC only - Cal04 challenge antibody responses.

[0069] FIG.ll. Microarray-Based Immunomonitoring of NHP responses to Flu

Challenge.

[0070] FIG.12. DC-targeting-NP5 + Poly ICLC mitigates Day 6 signature perturbations.

[0071] FIG.13. NHP De-targeting Influenza HAl + Poly ICLC vaccine studies.

[0072] FIG.14. NHP CD40-targeting Influenza HAl + Poly ICLC vaccine, NP- and

HAl-specific T cell responses via IFNgamma-ELISPOT.

[0073] FIG.15. NHP CD40-HA1 + Poly ICLC vaccine, HAl -specific serum IgG responses.

[0074] FIG.16. NHP DC-targeting Influenza HAl + Poly ICLC vaccines HA1- specific serum IgG responses. [0075] FIG.17. NHP DC-targeting Influenza HAl + Poly ICLC vaccines- serum HAl titers.

[0076] FIG.18. Targeting-HA+ Poly ICLC injection results in a signature perturbation 6 weeks following vaccination and reduction of both Day 1 and Day 6 responses to Cal04 challenge.

[0077] FIG.19. NHP De-targeting Influenza HAl-Flagellin vaccine studies.

[0078] FIG.20. NHP DC-targeting Influenza HAl- Flagellin vaccines, serum anti- HA1 IgG responses

[0079] FIG.21. NHP DC-targeting Influenza HAl- Flagellin vaccines, serum anti- Flagellin IgG responses.

[0080] FIG.22. NHP DC-targeting Influenza HAl - Flagellin vaccines, serum HAl titers.

[0081] FIG.23. NHP DC-targeting Influenza HAl- Flagellin vaccines, serum micro- neutralization titers.

[0082] FIG.24. Targeting-HA-Flagellin vaccines attenuate mRNA changes from live virus challenge.

[0083] FIG.25. NP-and HAl -specific serum IgG responses in NHP primed with live virus then given 100 micrograms of antiDectin-l -NP +/-Poly ICLC.

[0084] FIG.26. NP-specific T cell responses in NHP primed with live or killed virus then given a single dose of aDectin-l-NP + Poly ICLC.

[0085] FIG.27. Activation of memory CD8+ T cells

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

I. INFLUENZA VACCINE TECHNOLOGY

[0086] Methods and compositions are provided to generate an immune response in a subject against one or more influenza antigens in order to protect against or treat for infection by influenza. Dendritic cells (DCs) are antigen-presenting cells that play a key role in regulating antigen-specific immunity (Mellman and Steinman 2001), (Banchereau, Briere et al. 2000), (Cella, Sallusto et al. 1997). DCs capture antigens, process them into peptides, and present these to T cells. Therefore delivering antigens directly to DC is a focus area for developing vaccines. Provided herein are vaccine compositions containing influenza antigens for delivery to DC in order to initiate an immune response or generate a protective immune response against influenza or to generate an immune response such that there is memory in the subject to generate a protective immune response later.

[0087] Such technology and embodiments are described in the following U.S. Patent Publications 20120282281 (Agents that Engage Antigen-Presenting Cells Through Dendritic Cell Asialoglycoprotein Receptor (DC-ASGPR)); 20120244155 (Dendritic Cells (DCs) Targeting for Tuberculosis (TB) Vaccine); 20120237513 (Vaccines Based on Targeting Antigen to DCIR Expressed on Antigen-Presenting Cells); 20120231023 (Novel Vaccine Adjuvants Based on Targeting Adjuvants to Antibodies Directly to Antigen-Presenting Cells); 20120213768 (Diagnostic and Therapeutic Uses for B Cell Maturation Antigen); 20120128710 (Enhancement of Pathogen-Specific Memory Thl7 Cell Responses); 20120121592 (Targeting Antigens to Human Dendritic Cells Via DC-Asialoglycoprotein Receptor to Produce IL-10 Regulatory T-Cells; 20120039916 (NOVEL VACCINE ADJUVANTS BASED ON TARGETING ADJUVANTS TO ANTIBODIES DIRECTLY TO ANTIGEN-PRESENTING CELLS); 20120035240 (CONSERVED HBV AND HCV SEQUENCES USEFUL FOR GENE SILENCING); 20120020990 (ISOLATED MAMMALIAN MONOCYTE CELL GENES; RELATED REAGENTS); 20120004643 (Vaccines Based on Targeting Antigen to DCIR Expressed on Antigen-Presenting Cells); 201 10274653 (DENDRITIC CELL IMMUNORECEPTORS (DCIR)-MEDIATED CROSSPRIMING OF HUMAN CD8+ T CELLS); 201 10081343 (VACCINES DIRECTED TO LANGERHANS CELLS); 201003301 15 (Multivariable Antigens Complexed with Targeting Humanized Monoclonal Antibody); 20100322929 (ANTIGEN PRESENTING CELL TARGETED CANCER VACCINES); 201002971 14 (ANTIGEN PRESENTING CELL TARGETED VACCINES); 20100291082 (ANTIGEN PRESENTING CELL TARGETED ANTI-VIRAL VACCINES); 20100239575 (ANTI-CD40 ANTIBODIES AND USES THEREOF); 20100209907 (ISOLATED MAMMALIAN MONOCYTE CELL GENES; RELATED REAGENTS); 20100135994 (HIV VACCINE BASED ON TARGETING MAXIMIZED GAG AND NEF TO DENDRITIC CELLS); 20080267984 (Activation of Human Antigen-Presenting Cells Through Dendritic Cell Lectin-Like Oxidized LDL Receptor- 1 (LOX-1 )); 20080254047 (Activation of Human Antigen- Presenting Cells Through CLEC-6); 20080254044 (Multivariable Antigens Complexed with Targeting Humanized Monoclonal Antibody); 20080241 170 (Vaccines Based on Targeting Antigen to DCIR Expressed on Antigen-Presenting Cells); 20080233140 (Therapeutic Applications of Activation of Human Antigen-Presenting Cells Through Dectin-1); 20080206262 (Agents That Engage Antigen-Presenting Cells Through Dendritic Cell Asialoglycoprotein Receptor (DC-ASGPR)); 20080070854 (Conserved Hbv and Hcv Sequences Useful for Gene Silencing); 20050287582 (Antibodies that specifically bind to FDF03); 20050059808 (Isolated mammalian monocyte cell genes; related reagents); 20040143858 (Isolated mammalian monocyte cell genes; related reagents); 20030105303 (Isolated mammalian monocyte cell genes; related reagents); and, 20020161218 (Hepatitis C virus vaccine), all of which are hereby incorporated by reference.

II. NUCLEIC ACIDS

[0088] In certain embodiments, there are recombinant nucleic acids encoding the proteins, polypeptides, or peptides described herein. Polynucleotides contemplated for use in methods and compositions include those encoding antibodies against DC receptors (also referred to as anti-DC antibodies and DC targeting antibodies) or binding portions thereof.

[0089] As used in this application, the term "polynucleotide" refers to a nucleic acid molecule that either is recombinant or has been isolated free of total genomic nucleic acid. Included within the term "polynucleotide" are oligonucleotides (nucleic acids 100 residues or fewer in length), recombinant vectors, including, for example, plasmids, cosmids, phage, viruses, and the like. Polynucleotides include, in certain aspects, regulatory sequences, isolated substantially away from their naturally occurring genes or protein encoding sequences. Polynucleotides may be single-stranded (coding or antisense) or double-stranded, and may be RNA, DNA (genomic, cDNA or synthetic), analogs thereof, or a combination thereof. Additional coding or non-coding sequences may, but need not, be present within a polynucleotide.

[0090] In this respect, the term "gene," "polynucleotide," or "nucleic acid" is used to refer to a nucleic acid that encodes a protein, polypeptide, or peptide (including any sequences required for proper transcription, post-translational modification, or localization). As will be understood by those in the art, this term encompasses genomic sequences, expression cassettes, cDNA sequences, and smaller engineered nucleic acid segments that express, or may be adapted to express, proteins, polypeptides, domains, peptides, fusion proteins, and mutants. A nucleic acid encoding all or part of a polypeptide may contain a contiguous nucleic acid sequence encoding all or a portion of such a polypeptide. It also is contemplated that a particular polypeptide may be encoded by nucleic acids containing variations having slightly different nucleic acid sequences but, nonetheless, encode the same or substantially similar protein (see above).

[0091] In particular embodiments, there are isolated nucleic acid segments and recombinant vectors incorporating nucleic acid sequences that encode a polypeptide (e.g., an antibody or fragment thereof) that binds to DC receptors. The term "recombinant" may be used in conjunction with a polypeptide or the name of a specific polypeptide, and this generally refers to a polypeptide produced from a nucleic acid molecule that has been manipulated in vitro or that is a replication product of such a molecule.

[0092] The nucleic acid segments, regardless of the length of the coding sequence itself, may be combined with other nucleic acid sequences, such as promoters, polyadenylation signals, additional restriction enzyme sites, multiple cloning sites, other coding segments, and the like, such that their overall length may vary considerably. It is therefore contemplated that a nucleic acid fragment of almost any length may be employed, with the total length preferably being limited by the ease of preparation and use in the intended recombinant nucleic acid protocol. In some cases, a nucleic acid sequence may encode a polypeptide sequence with additional heterologous coding sequences, for example to allow for purification of the polypeptide, transport, secretion, post-translational modification, or for therapeutic benefits such as targeting or efficacy. As discussed above, a tag or other heterologous polypeptide may be added to the modified polypeptide-encoding sequence, wherein "heterologous" refers to a polypeptide that is not the same as the modified polypeptide.

[0093] In certain embodiments, there are polynucleotide variants having substantial identity to the sequences disclosed herein; those comprising at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% or higher sequence identity, including all values and ranges there between, compared to a polynucleotide sequence provided herein using the methods described herein {e.g., BLAST analysis using standard parameters). In certain aspects, the isolated polynucleotide will comprise a nucleotide sequence encoding a polypeptide that has at least 90%, preferably 95% and above, identity to an amino acid sequence described herein, over the entire length of the sequence; or a nucleotide sequence complementary to said isolated polynucleotide.

Vectors

[0094] Polypeptides may be encoded by a nucleic acid molecule. The nucleic acid molecule can be in the form of a nucleic acid vector. The term "vector" is used to refer to a carrier nucleic acid molecule into which a heterologous nucleic acid sequence can be inserted for introduction into a cell where it can be replicated and expressed. A nucleic acid sequence can be "heterologous," which means that it is in a context foreign to the cell in which the vector is being introduced or to the nucleic acid in which is incorporated, which includes a sequence homologous to a sequence in the cell or nucleic acid but in a position within the host cell or nucleic acid where it is ordinarily not found. Vectors include DNAs, R As, plasmids, cosmids, viruses (bacteriophage, animal viruses, and plant viruses), and artificial chromosomes (e.g., YACs). One of skill in the art would be well equipped to construct a vector through standard recombinant techniques (for example Sambrook et al., 2001 ; Ausubel et al., 1996, both incorporated herein by reference). Vectors may be used in a host cell to produce an antibody that binds a dendritic cell receptor.

[0095] The term "expression vector" refers to a vector containing a nucleic acid sequence coding for at least part of a gene product capable of being transcribed. In some cases, RNA molecules are then translated into a protein, polypeptide, or peptide. Expression vectors can contain a variety of "control sequences," which refer to nucleic acid sequences necessary for the transcription and possibly translation of an operably linked coding sequence in a particular host organism. In addition to control sequences that govern transcription and translation, vectors and expression vectors may contain nucleic acid sequences that serve other functions as well and are described herein.

Host Cells

[0096] As used herein, the terms "cell," "cell line," and "cell culture" may be used interchangeably. All of these terms also include their progeny, which is any and all subsequent generations. It is understood that all progeny may not be identical due to deliberate or inadvertent mutations. In the context of expressing a heterologous nucleic acid sequence, "host cell" refers to a prokaryotic or eukaryotic cell, and it includes any transformable organism that is capable of replicating a vector or expressing a heterologous gene encoded by a vector. A host cell can, and has been, used as a recipient for vectors or viruses. A host cell may be "transfected" or "transformed," which refers to a process by which exogenous nucleic acid, such as a recombinant protein-encoding sequence, is transferred or introduced into the host cell. A transformed cell includes the primary subject cell and its progeny.

[0097] Some vectors may employ control sequences that allow it to be replicated and/or expressed in both prokaryotic and eukaryotic cells. One of skill in the art would further understand the conditions under which to incubate all of the above described host cells to maintain them and to permit replication of a vector. Also understood and known are techniques and conditions that would allow large-scale production of vectors, as well as production of the nucleic acids encoded by vectors and their cognate polypeptides, proteins, or peptides.

Expression Systems

[0098] Numerous expression systems exist that comprise at least a part or all of the compositions discussed above. Prokaryote- and/or eukaryote -based systems can be employed for use with an embodiment to produce nucleic acid sequences, or their cognate polypeptides, proteins and peptides. Many such systems are commercially and widely available.

[0099] The insect cell/baculovirus system can produce a high level of protein expression of a heterologous nucleic acid segment, such as described in U.S. Patents 5,871,986, 4,879,236, both herein incorporated by reference, and which can be bought, for example, under the name MAXBAC® 2.0 from INVITROGEN® and BACPACK™ BACULOVIRUS EXPRESSION SYSTEM FROM CLONTECH®.

[00100] In addition to the disclosed expression systems, other examples of expression systems include STRATAGENE® ' s COMPLETE CONTROL Inducible Mammalian Expression System, which involves a synthetic ecdysone-inducible receptor, or its pET Expression System, an E. coli expression system. Another example of an inducible expression system is available from INVITROGEN ^® , which carries the T-REX™ (tetracycline -regulated expression) System, an inducible mammalian expression system that uses the full-length CMV promoter. INVITROGEN ^® also provides a yeast expression system called the Pichia methanolica Expression System, which is designed for high-level production of recombinant proteins in the methylotrophic yeast Pichia methanolica. One of skill in the art would know how to express a vector, such as an expression construct, to produce a nucleic acid sequence or its cognate polypeptide, protein, or peptide.

HI. PROTEINACEOUS COMPOSITIONS

[00101] Substitutional variants typically contain the exchange of one amino acid for another at one or more sites within the protein, and may be designed to modulate one or more properties of the polypeptide, with or without the loss of other functions or properties. Substitutions may be conservative, that is, one amino acid is replaced with one of similar shape and charge. Conservative substitutions are well known in the art and include, for example, the changes of: alanine to serine; arginine to lysine; asparagine to glutamine or histidine; aspartate to glutamate; cysteine to serine; glutamine to asparagine; glutamate to aspartate; glycine to proline; histidine to asparagine or glutamine; isoleucine to leucine or valine; leucine to valine or isoleucine; lysine to arginine; methionine to leucine or isoleucine; phenylalanine to tyrosine, leucine or methionine; serine to threonine; threonine to serine; tryptophan to tyrosine; tyrosine to tryptophan or phenylalanine; and valine to isoleucine or leucine. Alternatively, substitutions may be non-conservative such that a function or activity of the polypeptide is affected. Non-conservative changes typically involve substituting a residue with one that is chemically dissimilar, such as a polar or charged amino acid for a nonpolar or uncharged amino acid, and vice versa. [00102] Proteins may be recombinant, or synthesized in vitro. Alternatively, a non-recombinant or recombinant protein may be isolated from bacteria. It is also contemplated that a bacteria containing such a variant may be implemented in compositions and methods. Consequently, a protein need not be isolated.

[00103] The term "functionally equivalent codon" is used herein to refer to codons that encode the same amino acid, such as the six codons for arginine or serine, and also refers to codons that encode biologically equivalent amino acids (see Table, below). Codon Table

Amino Acids Codons

Alanine Ala A GCA GCC GCG GCU

Cysteine Cys C UGC UGU

Aspartic acid Asp D GAC GAU

Glutamic acid Glu E GAA GAG

Phenylalanine Phe F UUC UUU

Glycine Gly G GGA GGC GGG GGU

Histidine His H CAC CAU

Isoleiicine He I AUA AUC AUU

Lysine Lys K AAA AAG

Leucine Leu L UUA UUG CUA CUC CUG CUU

Methionine Met M AUG

Asparagine Asn N AAC AAU

Proline Pro P CCA CCC CCG CCU

Glutamine Gin Q CAA CAG

Arginine Arg R AGA AGG CGA CGC CGG CGU

Serine Ser S AGC AGU UCA UCC UCG UCU

Threonine Thr T ACA ACC ACG ACU

Valine Val V GUA GUC GUG GUU

Tryptophan Trp w UGG

Tyrosine Tyr Y UAC UAU

[00104] It also will be understood that amino acid and nucleic acid sequences may include additional residues, such as additional N- or C-terminal amino acids, or 5' or 3' sequences, respectively, and yet still be essentially as set forth in one of the sequences disclosed herein, so long as the sequence meets the criteria set forth above, including the maintenance of biological protein activity where protein expression is concerned. The addition of terminal sequences particularly applies to nucleic acid sequences that may, for example, include various non-coding sequences flanking either of the 5' or 3' portions of the coding region.

[00105] The following is a discussion based upon changing of the amino acids of a protein to create an equivalent, or even an improved, second-generation molecule. For example, certain amino acids may be substituted for other amino acids in a protein structure without appreciable loss of interactive binding capacity with structures such as, for example, antigen-binding regions of antibodies or binding sites on substrate molecules. Since it is the interactive capacity and nature of a protein that defines that protein's biological functional activity, certain amino acid substitutions can be made in a protein sequence, and in its underlying DNA coding sequence, and nevertheless produce a protein with like properties. It is thus contemplated by the inventors that various changes may be made in the DNA sequences of genes without appreciable loss of their biological utility or activity.

[00106] In making such changes, the hydropathic index of amino acids may be considered. The importance of the hydropathic amino acid index in conferring interactive biologic function on a protein is generally understood in the art (Kyte and Doolittle, 1982). It is accepted that the relative hydropathic character of the amino acid contributes to the secondary structure of the resultant protein, which in turn defines the interaction of the protein with other molecules, for example, enzymes, substrates, receptors, DNA, antibodies, antigens, and the like. [00107] It also is understood in the art that the substitution of like amino acids can be made effectively on the basis of hydrophilicity. U.S. Patent 4,554,101, incorporated herein by reference, states that the greatest local average hydrophilicity of a protein, as governed by the hydrophilicity of its adjacent amino acids, correlates with a biological property of the protein. It is understood that an amino acid can be substituted for another having a similar hydrophilicity value and still produce a biologically equivalent and immunologically equivalent protein.

[00108] As outlined above, amino acid substitutions generally are based on the relative similarity of the amino acid side-chain substituents, for example, their hydrophobicity, hydrophilicity, charge, size, and the like. Exemplary substitutions that take into consideration the various foregoing characteristics are well known and include: arginine and lysine; glutamate and aspartate; serine and threonine; glutamine and asparagine; and valine, leucine and isoleucine.

[00109] It is contemplated that in compositions there is between about 0.001 mg and about 10 mg of total polypeptide, peptide, and/or protein per ml. Thus, the concentration of protein in a composition can be about, at least about or at most about 0.001, 0.010, 0.050, 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0 mg/ml or more (or any range derivable therein). Of this, about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99, 100% may be an antibody that targets DC, and may be used in combination with other proteins, antibodies or protein-binding antibodies described herein.

Polypeptides and Polypeptide Production

[00110] Embodiments involve polypeptides, peptides, and proteins and immunogenic fragments thereof for use in various aspects described herein. For example, specific antibodies are assayed for or used in binding to DC receptors and presenting Influenza virus antigens. In specific embodiments, all or part of proteins described herein can also be synthesized in solution or on a solid support in accordance with conventional techniques. Various automatic synthesizers are commercially available and can be used in accordance with known protocols. See, for example, Stewart and Young, (1984); Tarn et al, (1983); Merrifield, (1986); and Barany and Merrifield (1979), each incorporated herein by reference. Alternatively, recombinant DNA technology may be employed wherein a nucleotide sequence that encodes a peptide or polypeptide is inserted into an expression vector, transformed or transfected into an appropriate host cell and cultivated under conditions suitable for expression.

[00111] One embodiment includes the use of gene transfer to cells, including microorganisms, for the production and/or presentation of proteins. The gene for the protein of interest may be transferred into appropriate host cells followed by culture of cells under the appropriate conditions. A nucleic acid encoding virtually any polypeptide may be employed. The generation of recombinant expression vectors, and the elements included therein, are discussed herein. Alternatively, the protein to be produced may be an endogenous protein normally synthesized by the cell used for protein production.

[00112] In a certain aspects a DC receptor fragment comprises substantially all of the extracellular domain of a protein which has at least 85% identity, at least 90% identity, at least 95% identity, or at least 91-99% identity, including all values and ranges there between, to a sequence selected over the length of the fragment sequence.

[00113] Also included in immunogenic compositions are fusion proteins composed of Influenza virus antigens, or immunogenic fragments of Influenza virus antigens (e.g. , NP5, HA1). Alternatively, embodiments also include individual fusion proteins of Influenza virus proteins or immunogenic fragments thereof, as a fusion protein with heterologous sequences such as a provider of T-cell epitopes or purification tags, for example: β-galactosidase, glutathione-S-transferase, 6xHis, green fluorescent proteins (GFP), epitope tags such as FLAG, myc tag, poly histidine, or viral surface proteins such as influenza virus haemagglutinin, or bacterial proteins such as tetanus toxoid, diphtheria toxoid, CRM 197. Antibodies and Antibody-Like Molecules

[00114] In certain aspects, one or more antibodies or antibody-like molecules

(e.g., polypeptides comprising antibody CDR domains) may be obtained or produced which have a specificity for a DC receptor. These antibodies may be used in various diagnostic or therapeutic applications described herein. [00115] As used herein, the term "antibody" is intended to refer broadly to any immunologic binding agent such as IgG, IgM, IgA, IgD and IgE as well as polypeptides comprsing antibody CDR domains that retain antigen binding activity. Thus, the term "antibody" is used to refer to any antibody-like molecule that has an antigen binding region, and includes antibody fragments such as Fab', Fab, F(ab')2, single domain antibodies (DABs), Fv, scFv (single chain Fv), and polypeptides with antibody CDRs, scaffolding domains that display the CDRs (e.g., anticalins) or a nanobody. For example, the nanobody can be antigen-specific VHH (e.g., a recombinant VHH) from a camelid IgG2 or IgG3, or a CDR-displaying frame from such camelid Ig. The techniques for preparing and using various antibody-based constructs and fragments are well known in the art. Means for preparing and characterizing antibodies are also well known in the art (See, e.g., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988; incorporated herein by reference).

[00116] "Mini-antibodies" or "minibodies" are also contemplated for use with embodiments. Minibodies are sFv polypeptide chains which include oligomerization domains at their C-termini, separated from the sFv by a hinge region (Pack et al., 1992). The oligomerization domain comprises self-associating a-helices, e.g., leucine zippers, that can be further stabilized by additional disulfide bonds. The oligomerization domain is designed to be compatible with vectorial folding across a membrane, a process thought to facilitate in vivo folding of the polypeptide into a functional binding protein. Generally, minibodies are produced using recombinant methods well known in the art. See, e.g., Pack et al. (1992); Cumber et al. (1992). [00117] Antibody-like binding peptidomimetics are also contemplated in embodiments. Liu et al.(2003) describe "antibody like binding peptidomimetics" (ABiPs), which are peptides that act as pared-down antibodies and have certain advantages of longer serum half-life as well as less cumbersome synthesis methods. [00118] Alternative scaffolds for antigen binding peptides, such as CDRs are also available and can be used to generate DC receptor-binding molecules in accordance with the embodiments. Generally, a person skilled in the art knows how to determine the type of protein scaffold on which to graft at least one of the CDRs arising from the original antibody. More particularly, it is known that to be selected such scaffolds must meet the greatest number of criteria as follows (Skerra, 2000): good phylogenetic conservation; known three- dimensional structure (as, for example, by crystallography, NMR spectroscopy or any other technique known to a person skilled in the art); small size; few or no post-transcriptional modifications; and/or easy to produce, express and purify.

[00119] The origin of such protein scaffolds can be, but is not limited to, the structures selected among: fibronectin and preferentially fibronectin type III domain 10, lipocalin, anticalin (Skerra, 2001), thioredoxin A or proteins with a repeated motif such as the "ankyrin repeat" (Kohl et al, 2003), the "armadillo repeat", the "leucine-rich repeat" and the "tetratricopeptide repeat". For example, anticalins or lipocalin derivatives are a type of binding proteins that have affinities and specificities for various target molecules; such proteins are described in US Patent Publication Nos. 20100285564, 20060058510, 20060088908, 20050106660, and PCT Publication No. WO2006/056464, incorporated herein by reference.

[00120] Scaffolds derived from toxins such as, for example, toxins from scorpions, insects, plants, mollusks, etc., and the protein inhibiters of neuronal NO synthase (PIN) may also be used in certain aspects.

[00121] Monoclonal antibodies (MAbs) are recognized to have certain advantages, e.g., reproducibility and large-scale production. Embodiments include monoclonal antibodies of the human, murine, monkey, rat, hamster, rabbit and chicken origin.

[00122] "Humanized" antibodies are also contemplated, as are chimeric antibodies from mouse, rat, or other species, bearing human constant and/or variable region domains, bispecific antibodies, recombinant and engineered antibodies and fragments thereof. As used herein, the term "humanized" immunoglobulin refers to an immunoglobulin comprising a human framework region and one or more CDR's from a non-human (usually a mouse or rat) immunoglobulin. The non-human immunoglobulin providing the CDR's is called the "donor" and the human immunoglobulin providing the framework is called the "acceptor". A "humanized antibody" is an antibody comprising a humanized light chain and a humanized heavy chain immunoglobulin. In order to describe antibodies of some embodiments, the strength with which an antibody molecule binds an epitope, known as affinity, can be measured. The affinity of an antibody may be determined by measuring an association constant (Ka) or dissociation constant (Kd). Antibodies deemed useful in certain embodiments may have an association constant of about, at least about, or at most about 10e6, 10e7, 10e8, 10e9 or l OelO M or any range derivable therein. Similarly, in some embodiments antibodies may have a dissoaciation constant of about, at least about or at most about 10e-6, 10e-7, 10e-8, 10e-9 or l Oe- 10. M or any range derivable therein. These values are reported for antibodies discussed herein and the same assay may be used to evaluate the binding properties of such antibodies

[00123] In certain embodiments, a polypeptide that specifically binds to DC receptors is able to bind a DC receptor on the surface of the cells and present an Influenza virus antigen that allows the generation of a robust immune response. Moreover, in some embodiments, the polypeptide that is used can provided protective immunity against Influenza.

1. Methods for Generating Antibodies

[00124] Methods for generating antibodies (e.g., monoclonal antibodies and/or monoclonal antibodies) are known in the art. Briefly, a polyclonal antibody is prepared by immunizing an animal with a DC receptor polypeptide or a portion thereof in accordance with embodiments and collecting antisera from that immunized animal.

[00125] A wide range of animal species can be used for the production of antisera. Typically the animal used for production of antisera is a rabbit, a mouse, a rat, a hamster, a guinea pig or a goat. The choice of animal may be decided upon the ease of manipulation, costs or the desired amount of sera, as would be known to one of skill in the art. It will be appreciated that antibodies can also be produced transgenically through the generation of a mammal or plant that is transgenic for the immunoglobulin heavy and light chain sequences of interest and production of the antibody in a recoverable form therefrom. In connection with the transgenic production in mammals, antibodies can be produced in, and recovered from, the milk of goats, cows, or other mammals. See, e.g., U.S. Pat. Nos. 5,827,690, 5,756,687, 5,750,172, and 5,741 ,957.

[00126] As is also well known in the art, the immunogenicity of a particular immunogen composition can be enhanced by the use of non-specific stimulators of the immune response, known as adjuvants. Suitable adjuvants include any acceptable immunostimulatory compound, such as cytokines, chemokines, cofactors, toxins, plasmodia, synthetic compositions or vectors encoding such adjuvants. Adjuvants may be chemically conjugated to antibodies or antigen-delivering antibody fusions proteins. Alternatively adjuvants may be recombinantly fused to antibodies or antigen-delivering antibody fusions proteins. In certain aspects, adjuvants may be chemically conjugated or recombinantly fused to Cohesin or Dockerin to allow for binding to any other molecule containing a corresponding Dockerin or Cohesin binding domain.

[00127] Adjuvants that may be used in accordance with embodiments include, but are not limited to, IL-1, IL-2, IL-4, IL-7, IL-12, -interferon, GMCSP, BCG, aluminum hydroxide, Poly ICLC, MDP compounds, such as thur-MDP and nor-MDP, CGP (MTP-PE), lipid A, and monophosphoryl lipid A (MPL). RIBI, which contains three components extracted from bacteria, MPL, trehalose dimycolate (TDM) and cell wall skeleton (CWS) in a 2% squalene/Tween 80 emulsion is also contemplated. MHC antigens may even be used. Exemplary adjuvants may include complete Freund's adjuvant (a non-specific stimulator of the immune response containing killed Mycobacterium tuberculosis), incomplete Freund's adjuvants and/or aluminum hydroxide adjuvant. [00128] In addition to adjuvants, it may be desirable to coadminister biologic response modifiers (BRM), which have been shown to upregulate T cell immunity or downregulate suppressor cell activity. Such BRMs include, but are not limited to, Cimetidine (CIM; 1200 mg/d) (Smith/Kline, PA); low-dose Cyclophosphamide (CYP; 300 mg/m2) (Johnson/ Mead, NJ), cytokines such as -interferon, IL-2, or IL- 12 or genes encoding proteins involved in immune helper functions, such as B-7. [00129] The amount of immunogen composition used in the production of antibodies varies upon the nature of the immunogen as well as the animal used for immunization. A variety of routes can be used to administer the immunogen including but not limited to subcutaneous, intramuscular, intradermal, intraepidermal, intravenous and intraperitoneal. The production of antibodies may be monitored by sampling blood of the immunized animal at various points following immunization.

[00130] A second, booster dose (e.g., provided in an injection), may also be given. The process of boosting and titering is repeated until a suitable titer is achieved. When a desired level of immunogenicity is obtained, the immunized animal can be bled and the serum isolated and stored, and/or the animal can be used to generate MAbs.

[00131] For production of rabbit polyclonal antibodies, the animal can be bled through an ear vein or alternatively by cardiac puncture. The removed blood is allowed to coagulate and then centrifuged to separate serum components from whole cells and blood clots. The serum may be used as is for various applications or else the desired antibody fraction may be purified by well-known methods, such as affinity chromatography using another antibody, a peptide bound to a solid matrix, or by using, e.g., protein A or protein G chromatography, among others.

[00132] MAbs may be readily prepared through use of well-known techniques, such as those exemplified in U.S. Patent 4,196,265, incorporated herein by reference. Typically, this technique involves immunizing a suitable animal with a selected immunogen composition, e.g., a purified or partially purified protein, polypeptide, peptide or domain, be it a wild-type or mutant composition. The immunizing composition is administered in a manner effective to stimulate antibody producing cells.

[00133] The methods for generating monoclonal antibodies (MAbs) generally begin along the same lines as those for preparing polyclonal antibodies. In some embodiments, Rodents such as mice and rats are used in generating monoclonal antibodies. In some embodiments, rabbit, sheep or frog cells are used in generating monoclonal antibodies. The use of rats is well known and may provide certain advantages (Goding, 1986, pp. 60 61). Mice (e.g., BALB/c mice)are routinely used and generally give a high percentage of stable fusions. [00134] The animals are injected with antigen, generally as described above.

The antigen may be mixed with adjuvant, such as Freund's complete or incomplete adjuvant. Booster administrations with the same antigen or DNA encoding the antigen may occur at approximately two-week intervals. As discussed in the Examples, the antigen may be altered compared to an antigen sequence found in nature.

[00135] Following immunization, somatic cells with the potential for producing antibodies, specifically B lymphocytes (B cells), are selected for use in the MAb generating protocol. These cells may be obtained from biopsied spleens, tonsils or lymph nodes, or from a peripheral blood sample. Generally, spleen cells are a rich source of antibody-producing cells that are in the dividing plasmablast stage. Typically, peripheral blood cells may be readily obtained, as peripheral blood is easily accessible.

[00136] In some embodiments, a panel of animals will have been immunized and the spleen of an animal with the highest antibody titer will be removed and the spleen lymphocytes obtained by homogenizing the spleen with a syringe. Typically, a spleen from

7 8

an immunized mouse contains approximately 5 x 10 to 2 x 10 lymphocytes.

[00137] The antibody producing B lymphocytes from the immunized animal are then fused with cells of an immortal myeloma cell, generally one of the same species as the animal that was immunized. Myeloma cell lines suited for use in hybridoma producing fusion procedures preferably are non antibody producing, have high fusion efficiency, and enzyme deficiencies that render then incapable of growing in certain selective media which support the growth of only the desired fused cells (hybridomas).

[00138] Any one of a number of myeloma cells may be used, as are known to those of skill in the art (Goding, pp. 65 66, 1986; Campbell, pp. 75 83, 1984). cites). For example, where the immunized animal is a mouse, one may use P3 X63/Ag8, X63 Ag8.653, NS l/l .Ag 4 1 , Sp210 Agl4, FO, NSO/U, MPC 1 1 , MPC1 1 X45 GTG 1.7 and S194/5XX0 Bui; for rats, one may use R210.RCY3, Y3 Ag 1.2.3, IR983F and 4B210; and U 266, GM1500 GRG2, LICR LON HMy2 and UC729 6 are all useful in connection with human cell fusions. See Yoo et al. (2002), for a discussion of myeloma expression systems.

[00139] One murine myeloma cell is the NS-1 myeloma cell line (also termed P3-NS-l-Ag4-l), which is readily available from the NIGMS Human Genetic Mutant Cell Repository by requesting cell line repository number GM3573. Another mouse myeloma cell line that may be used is the 8 azaguanine resistant mouse murine myeloma SP2/0 non producer cell line.

[00140] Methods for generating hybrids of antibody producing spleen or lymph node cells and myeloma cells usually comprise mixing somatic cells with myeloma cells in a 2: 1 proportion, though the proportion may vary from about 20: 1 to about 1 : 1 , respectively, in the presence of an agent or agents (chemical or electrical) that promote the fusion of cell membranes. Fusion methods using Sendai virus have been described by Kohler and Milstein (1975; 1976), and those using polyethylene glycol (PEG), such as 37% (v/v) PEG, by Gefter et al., (1977). The use of electrically induced fusion methods is also appropriate (Goding pp. 71 74, 1986).

[00141] Fusion procedures usually produce viable hybrids at low frequencies, about 1 x 10 ^"6 to 1 x 10 ^"8 . However, this does not pose a problem, as the viable, fused hybrids are differentiated from the parental, unfused cells (particularly the unfused myeloma cells that would normally continue to divide indefinitely) by culturing in a selective medium. The selective medium is generally one that contains an agent that blocks the de novo synthesis of nucleotides in the tissue culture media. Exemplary and preferred agents are aminopterin, methotrexate, and azaserine. Aminopterin and methotrexate block de novo synthesis of both purines and pyrimidines, whereas azaserine blocks only purine synthesis. Where aminopterin or methotrexate is used, the media is supplemented with hypoxanthine and thymidine as a source of nucleotides (HAT medium). Where azaserine is used, the media is supplemented with hypoxanthine.

[00142] A selection medium is HAT. Only cells capable of operating nucleotide salvage pathways are able to survive in HAT medium. The myeloma cells are defective in key enzymes of the salvage pathway, e.g., hypoxanthine phosphoribosyl transferase (HPRT), and they cannot survive. The B cells can operate this pathway, but they have a limited life span in culture and generally die within about two weeks. Therefore, the only cells that can survive in the selective media are those hybrids formed from myeloma and B cells.

[00143] This culturing provides a population of hybridomas from which specific hybridomas are selected. Typically, selection of hybridomas is performed by culturing the cells by single-clone dilution in microtiter plates, followed by testing the individual clonal supernatants (after about two to three weeks) for the desired reactivity. The assay should be sensitive, simple and rapid, such as radioimmunoassays, enzyme immunoassays, cytotoxicity assays, plaque assays, dot immunobinding assays, and the like.

[00144] The selected hybridomas would then be serially diluted and cloned into individual antibody producing cell lines, which clones can then be propagated indefinitely to provide MAbs. The cell lines may be exploited for MAb production in two basic ways. First, a sample of the hybridoma can be injected (often into the peritoneal cavity) into a histocompatible animal of the type that was used to provide the somatic and myeloma cells for the original fusion (e.g., a syngeneic mouse). Optionally, the animals are primed with a hydrocarbon, especially oils such as pristane (tetramethylpentadecane) prior to injection. The injected animal develops tumors secreting the specific monoclonal antibody produced by the fused cell hybrid. The body fluids of the animal, such as serum or ascites fluid, can then be tapped to provide MAbs in high concentration. Second, the individual cell lines could be cultured in vitro, where the MAbs are naturally secreted into the culture medium from which they can be readily obtained in high concentrations.

[00145] Further, expression of antibodies (or other moieties therefrom) from production cell lines can be enhanced using a number of known techniques. For example, the glutamine synthetase and DHFR gene expression systems are common approaches for enhancing expression under certain conditions. High expressing cell clones can be identified using conventional techniques, such as limited dilution cloning and Microdrop technology. The GS system is discussed in whole or part in connection with European Patent Nos. 0 216 846, 0 256 055, and 0 323 997 and European Patent Application No. 89303964.4.

[00146] MAbs produced by either means may be further purified, if desired, using filtration, centrifugation and various chromatographic methods such as HPLC or affinity chromatography. Fragments of the monoclonal antibodies can be obtained from the monoclonal antibodies so produced by methods which include digestion with enzymes, such as pepsin or papain, and/or by cleavage of disulfide bonds by chemical reduction. Alternatively, monoclonal antibody fragments can be synthesized using an automated peptide synthesizer. [00147] It is also contemplated that a molecular cloning approach may be used to generate monoclonal antibodies. In one embodiment, combinatorial immunoglobulin phagemid libraries are prepared from RNA isolated from the spleen of the immunized animal, and phagemids expressing appropriate antibodies are selected by panning using cells expressing the antigen and control cells. The advantages of this approach over conventional hybridoma techniques are that approximately 10e4 times as many antibodies can be produced and screened in a single round, and that new specificities are generated by H and L chain combination which further increases the chance of finding appropriate antibodies.

[00148] Another embodiment concerns producing antibodies, for example, as is found in U.S. Patent No. 6,091 ,001 , which describes methods to produce a cell expressing an antibody from a genomic sequence of the cell comprising a modified immunoglobulin locus using Cre-mediated site-specific recombination is disclosed. The method involves first transfecting an antibody-producing cell with a homology-targeting vector comprising a lox site and a targeting sequence homologous to a first DNA sequence adjacent to the region of the immunoglobulin loci of the genomic sequence which is to be converted to a modified region, so the first lox site is inserted into the genomic sequence via site-specific homologous recombination. Then the cell is transfected with a lox-targeting vector comprising a second lox site suitable for Cre-mediated recombination with the integrated lox site and a modifying sequence to convert the region of the immunoglobulin loci to the modified region. This conversion is performed by interacting the lox sites with Cre in vivo, so that the modifying sequence inserts into the genomic sequence via Cre-mediated site-specific recombination of the lox sites.

[00149] Alternatively, monoclonal antibody fragments can be synthesized using an automated peptide synthesizer, or by expression of full-length gene or of gene fragments in E. coli.

[00150] It is further contemplated that monoclonal antibodies may be further screened or optimized for properties relating to specificity, avidity, half-life, immunogenicity, binding association, binding disassociation, or overall functional properties relative to beinga treatment for infection. Thus, it is contemplated that monoclonal antibodies may have 1 , 2, 3, 4, 5, 6, or more alterations in the amino acid sequence of 1 , 2, 3, 4, 5, or 6 CDRs of monoclonal antibodies mAnti-LOX-1 15C4, mAnti-Dectin _1_15E2.5, mAnti- CD40 12E12.3F3, mAnti-LOX-1 1 C4K, mAnti-DCIR_9E8, mAnti-Langerin 15 10. It is contemplated that the amino acid in position 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 of CDR1, CDR2, CDR3, CDR4, CDR5, or CDR6 of the VJ or VDJ region of the light or heavy variable region of monoclonal antibodies mAnti-LOX-1 15C4, mAnti-Dectin_ l_l 5E2.5, mAnti- CD40_12E12.3F3, mAnti-LOX- 1 1 C4K, mAnti-DCIR_9E8, mAnti-Langerin_15 10 may have an insertion, deletion, or substitution with a conserved or non-conserved amino acid. Such amino acids that can either be substituted or constitute the substitution are disclosed above.

[00151] In some embodiments, fragments of a whole antibody can perform the function of binding antigens. Examples of binding fragments are (i) the Fab fragment constituted with the VL, VH, CL and CHI domains; (ii) the Fd fragment consisting of the VH and CHI domains; (iii) the Fv fragment constituted with the VL and VH domains of a single antibody; (iv) the dAb fragment (Ward, 1989; McCafferty et al, 1990; Holt et al., 2003), which is constituted with a VH or a VL domain; (v) isolated CDR regions; (vi) F(ab')2 fragments, a bivalent fragment comprising two linked Fab fragments (vii) single chain Fv molecules (scFv) , wherein a VH domain and a VL domain are linked by a peptide linker which allows the two domains to associate to form an antigen binding site (Bird et al., 1988; Huston et al., 1988); (viii) bispecific single chain Fv dimers (PCT US92/09965) and (ix) "diabodies", multivalent or multispecific fragments constructed by gene fusion (WO94/13804; Holliger et al., 1993) . Fv, scFv or diabody molecules may be stabilized by the incorporation of disulphide bridges linking the VH and VL domains (Reiter et al., 1996). Minibodies comprising a scFv joined to a CH3 domain may also be made (Hu et al. 1996). The citations in this paragraph are all incorporated by reference.

[00152] Antibodies also include bispecific antibodies. Bispecific or bifunctional antibodies form a second generation of monoclonal antibodies in which two different variable regions are combined in the same molecule (Holliger, P. & Winter, G. 1999 Cancer and metastasis rev. 18:41 1 -419, 1999). Their use has been demonstrated both in the diagnostic field and in the therapy field from their capacity to recruit new effector functions or to target several molecules on the surface of tumor cells. Where bispecific antibodies are to be used, these may be conventional bispecific antibodies, which can be manufactured in a variety of ways (Holliger et al, PNAS USA 90:6444-6448, 1993), e.g. prepared chemically or from hybrid hybridomas, or may be any of the bispecific antibody fragments mentioned above. These antibodies can be obtained by chemical methods (Glennie et al., 1987 J. Immunol. 139, 2367-2375; Repp et al., J. Hemat. 377-382, 1995) or somatic methods (Staerz U. D. and Bevan M. J. PNAS 83, 1986; et al., Method Enzymol. 121 :210-228, 1986) but likewise by genetic engineering techniques which allow the heterodimerization to be forced and thus facilitate the process of purification of the antibody sought (Merchand et al. Nature Biotech, 16:677-681 , 1998). Examples of bispecific antibodies include those of the BiTE™ technology in which the binding domains of two antibodies with different specificity can be used and directly linked via short flexible peptides. This combines two antibodies on a short single polypeptide chain. Diabodies and scFv can be constructed without an Fc region, using only variable domains, potentially reducing the effects of anti-idiotypic reaction. The citations in this paragraph are all incorporated by reference.

[00153] Bispecific antibodies can be constructed as entire IgG, as bispecific Fab '2, as Fab 'PEG, as diabodies or else as bispecific scFv. Further, two bispecific antibodies can be linked using routine methods known in the art to form tetravalent antibodies.

[00154] Bispecific diabodies, as opposed to bispecific whole antibodies, may also be particularly useful because they can be readily constructed and expressed in E. coli. Diabodies (and many other polypeptides such as antibody fragments) of appropriate binding specificities can be readily selected using phage display (WO94/13804) from libraries. If one arm of the diabody is to be kept constant, for instance, with a specificity directed against a DC receptor, then a library can be made where the other arm is varied and an antibody of appropriate specificity selected. Bispecific whole antibodies may be made by alternative engineering methods as described in Ridgeway et al, (Protein Eng., 9:616-621 , 1996), which is hereby incorporated by reference.

Antibody and Polypeptide Conjugates

[00155] Embodiments provide antibodies and antibody-like molecules against

DC receptors, polypeptides and peptides that are linked to at least one agent to form an antibody conjugate or payload or fusion. In order to increase the efficacy of antibody molecules as diagnostic or therapeutic agents, it is conventional to link or covalently bind or complex at least one desired molecule or moiety. Such a molecule or moiety may be, but is not limited to, at least one effector or reporter molecule. Effector molecules comprise molecules having a desired activity, e.g., cytotoxic activity. Non-limiting examples of effector molecules which have been attached to antibodies include toxins, therapeutic enzymes, antibiotics, radio-labeled nucleotides and the like. By contrast, a reporter molecule is defined as any moiety which may be detected using an assay. Non-limiting examples of reporter molecules which have been conjugated to antibodies include enzymes, radiolabels, haptens, fluorescent labels, phosphorescent molecules, chemiluminescent molecules, chromophores, luminescent molecules, photoaffmity molecules, colored particles or ligands, such as biotin.

[00156] Certain examples of antibody conjugates are those conjugates in which the antibody is linked to a detectable label. "Detectable labels" are compounds and/or elements that can be detected due to their specific functional properties, and/or chemical characteristics, the use of which allows the antibody to which they are attached to be detected, and/or further quantified if desired.

[00157] Antibody conjugates are in certain embodiments used as diagnostic agents. Antibody diagnostics generally fall within two classes, those for use in in vitro diagnostics, such as in a variety of immunoassays, and/or those for use in vivo diagnostic protocols, generally known as "antibody directed imaging". Many appropriate imaging agents are known in the art, as are methods for their attachment to antibodies (see, for e.g., U.S. Patent Nos. 5,021 ,236; 4,938,948; and 4,472,509, each incorporated herein by reference). The imaging moieties used can be paramagnetic ions; radioactive isotopes; fluorochromes; NMR-detectable substances; X-ray imaging.

[00158] In the case of paramagnetic ions, one might mention by way of example ions such as chromium (III), manganese (II), iron (III), iron (II), cobalt (II), nickel (II), copper (II), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), vanadium (II), terbium (III), dysprosium (III), holmium (III) and/or erbium (III), with gadolinium being particularly preferred. Ions useful in other contexts, such as X-ray imaging, include but are not limited to lanthanum (III), gold (III), lead (II), and especially bismuth (III).

[00159] In the case of radioactive isotopes for therapeutic and/or diagnostic application, one might use astatine ^{21 1} , carbon ¹⁴ , chromium ³¹ , chlorine ³⁶ , cobalt ⁵⁷ , cobalt ⁵⁸ , copper , Eu , gallium , hydrogen , iodine , iodine , iodine , indium , iron , phosphorus ³² , rhenium ¹⁸⁶ , rhenium ¹⁸⁸ , selenium ⁷⁵ , sulphur ³⁵ , technicium" and/or yttrium ⁹⁰ . ^{1 :>} I is often used in certain embodiments, and technicium" and/or indium ^{1 1 1} are also often used due to their low energy and suitability for long range detection. Radioactively labeled monoclonal antibodies may be produced according to well-known methods in the art. For instance, monoclonal antibodies can be iodinated by contact with sodium and/or potassium iodide and a chemical oxidizing agent such as sodium hypochlorite, or an enzymatic oxidizing agent, such as lactoperoxidase. Monoclonal antibodies may be labeled with technetium99m by ligand exchange process, for example, by reducing pertechnate with stannous solution, chelating the reduced technetium onto a Sephadex column and applying the antibody to this column. Alternatively, direct labeling techniques may be used, e.g., by incubating pertechnate, a reducing agent such as SNC1 ₂ , a buffer solution such as sodium- potassium phthalate solution, and the antibody. Intermediary functional groups which are often used to bind radioisotopes which exist as metallic ions to antibody are diethylenetriaminepentaacetic acid (DTP A) or ethylene diaminetetracetic acid (EDTA).

[00160] Among the fluorescent labels contemplated for use as conjugates include Alexa 350, Alexa 430, AMCA, BODIPY 630/650, BODIPY 650/665, BODIPY-FL, BODIPY-R6G, BODIPY-TMR, BODIPY-TRX, Cascade Blue, Cy3, Cy5,6-FAM, Fluorescein Isothiocyanate, HEX, 6-JOE, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, REG, Rhodamine Green, Rhodamine Red, Renographin, ROX, TAMRA, TET, Tetramethylrhodamine, and/or Texas Red, among others. [00161] Antibody conjugates include those intended primarily for use in vitro, where the antibody is linked to a secondary binding ligand and/or to an enzyme (an enzyme tag) that will generate a colored product upon contact with a chromogenic substrate. Examples of suitable enzymes include, but are not limited to, urease, alkaline phosphatase, (horseradish) hydrogen peroxidase or glucose oxidase. Preferred secondary binding ligands are biotin and/or avidin and streptavidin compounds. The use of such labels is well known to those of skill in the art and are described, for example, in U.S. Patents 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437; 4,275,149 and 4,366,241 ; each incorporated herein by reference.

[00162] Yet another known method of site-specific attachment of molecules to antibodies comprises the reaction of antibodies with hapten-based affinity labels. Essentially, hapten-based affinity labels react with amino acids in the antigen binding site, thereby destroying this site and blocking specific antigen reaction. However, this may not be advantageous since it results in loss of antigen binding by the antibody conjugate.

[00163] Molecules containing azido groups may also be used to form covalent bonds to proteins through reactive nitrene intermediates that are generated by low intensity ultraviolet light (Potter & Haley, 1983). In particular, 2- and 8-azido analogues of purine nucleotides have been used as site-directed photoprobes to identify nucleotide binding proteins in crude cell extracts (Owens & Haley, 1987; Atherton et al., 1985). The 2- and 8- azido nucleotides have also been used to map nucleotide binding domains of purified proteins (Khatoon et al., 1989; King et al., 1989; and Dholakia et al, 1989) and may be used as antibody binding agents.

[00164] Several methods are known in the art for the attachment or conjugation of an antibody to its conjugate moiety. Some attachment methods involve the use of a metal chelate complex employing, for example, an organic chelating agent such a diethylenetriaminepentaacetic acid anhydride (DTP A); ethylenetriaminetetraacetic acid; N- chloro-p-toluenesulfonamide; and/or tetrachloro-3 -6 -diphenylglycouril-3 attached to the antibody (U.S. Patent Nos. 4,472,509 and 4,938,948, each incorporated herein by reference). Monoclonal antibodies may also be reacted with an enzyme in the presence of a coupling agent such as glutaraldehyde or periodate. Conjugates with fluorescein markers are prepared in the presence of these coupling agents or by reaction with an isothiocyanate. In U.S. Patent No. 4,938,948, imaging of breast tumors is achieved using monoclonal antibodies and the detectable imaging moieties are bound to the antibody using linkers such as methyl-p- hydroxybenzimidate or N-succinimidyl-3-(4-hydroxyphenyl)propionate.

[00165] In some embodiments, derivatization of immunoglobulins by selectively introducing sulfhydryl groups in the Fc region of an immunoglobulin, using reaction conditions that do not alter the antibody combining site are contemplated. Antibody conjugates produced according to this methodology are disclosed to exhibit improved longevity, specificity and sensitivity (U.S. Pat. No. 5,196,066, incorporated herein by reference). Site-specific attachment of effector or reporter molecules, wherein the reporter or effector molecule is conjugated to a carbohydrate residue in the Fc region have also been disclosed in the literature (O'Shannessy et al , 1987). This approach has been reported to produce diagnostically and therapeutically promising antibodies which are currently in clinical evaluation.

IV. DENDRITIC CELL VACCINES

[00166] As used herein, "Dendritic Cells" (DCs) refers to any member of a diverse population of morphologically similar cell types found in lymphoid or non-lymphoid tissues. These cells are characterized by their distinctive morphology, high levels of surface MHC-class II expression (Steinman, et al., Ann. Rev. Immunol. 9:271 (1991); incorporated herein by reference for its description of such cells). These cells can be isolated from a number of tissue sources, and conveniently, from peripheral blood, as described herein.

Influenza antigens

[00167] In certain embodiments any influenza antigen may be recombinantly fused or chemically conjugated to a DC targeting antibody to deliver the influenza antigen to a dendritic cell. An influenza antigen may be any influenza antigen that when fused to a DC targeting antibody is sufficient to evoke an immune response in a subject. In certain embodiments the immune response is sufficient to protect a subject from infection with an influenza virus. In other embodiments protection afforded by the antigen/targeting antibody fusion is sufficient to depress or prevent symptoms associated with influenza infection ("flu").

[00168] In some embodiments the influenza antigen is a hemagglutinin (HA) antigen. The HA antigen may be of any of three types of Influenza virus, specifically Influenza A, Influenza B or Influenza C. In some embodiments the HA antigen is from a "swine flu" influenza virus or a "bird flu" influenza virus. In yet other aspects the HA antigen may be modified such that a specific domain has been removed to improve antigenicity. One specific example of such a modification is a so-called "headless" HA antigen.

[00169] In certain aspects, the HA antigen may be one of 17 identified HA antigens. In some embodiments the HA antigen may be HA1, HA2, HA3, HA4, HA5, HA6, HA7, HA8, HA9, HA10, HA1 1 , HA12, HA13, HA14, HA15, HA16 or HA17.

[00170] In some embodiments the influenza antigen is a nucleoprotein antigen.

In certain aspects the nucleoprotein (NP) antigen may be of nucleoprotein Group 1 , Group 2, Group 3, Group 4 or Group 5. In other embodiments the NP antigen is from any of the three influenza RNA virus genera (Influenza A, B or C). In yet other embodiments the NP antigen is from any serotype known to infect humans. In some embodiments the NP antigen is from influenza serotype H1N1 , H2N2, H3N2, H5N1 , H7N7, H1N2, H9N2, H7N2, H7N3 or H10N7.

Dendritic cell specific antibodies [00171] In certain aspects, antibodies used to target Influenza antigens to dendritic cells are dendritic cell specific antibodies. Some of the antibodies that may be used for this purpose are known in the art.

[00172] In some embodiments anti-DCIR antibodies are used to target Influenza antigens to dendritic cells. One example includes anti-dendritic cell immunoreceptor monoclonal antibody conjugates, wherein the conjugate comprises antigenic peptides that are loaded or chemically coupled to the antibody. Such antibodies are described in US 2008/0241 170 and US 201 1/274653, each of which is incorporated herein by reference. [00173] In other embodiments anti-CD40 antibodies are used to target

Influenza antigens to dendritic cells. Compositions and methods for the expression, secretion and use of anti-CD40 antibodies as vaccines and antigen delivery vectors with one linked antigenic peptides are described in WO 2010/104761 ; all methods and the contents of which are incorporated herein by reference. [00174] In certain aspects anti-LOX-1 antibodies are used to target Influenza antigens to dendritic cells. One example of such an antibody can be used to target the LOX-1 receptor on immune cells and increase the effectiveness of antigen presentation by LOX-1 expressing antigen presenting cells. Examples of such LOX-1 antibodies are described in WO 2008/103953, the contents of which are incorporated herein by reference. [00175] In other aspects anti-CLEC-6 antibodies are used to target Influenza antigens to dendritic cells. One example of such antibodies include anti-CLEC-6 antibodies used to increase the effectiveness of antigen presentation by CLEC-6 expressing antigen presenting cells. Such antibodies are described in WO 2008/103947, the methods and contents of which are incorporated herein by reference. [00176] In yet other embodiments anti-Dectin-1 antibodies are used to target

Influenza antigens to dendritic cells. Anti-Dectin-1 antibodies that increase the effectiveness of antigen presentation by Dectin-1 expressing antigen presenting cells are described in WO 2008/1 18587, the contents of which are incorporated herein by reference.

[00177] In other aspects anti-Langerin antibodies are used to target Influenza antigens to dendritic cells. One example of such antibodies include anti-Langerin antibodies used to increase the effectiveness of antigen presentation by Langerin expressing antigen presenting cells. Anti-Langerin antibodies are disclosed in US 201 1/0081343, the contents of which are incorporated herein by reference.

Peptide Linkers [00178] In certain aspects, peptide linkers are used to link dendritic cell specific antibodies and Influenza antigens to be presented. Peptide linkers may incorporate glycosylation sites or introduce secondary structure. Additionally these linkers increase the efficiency of expression or stability of the fusion protein and as a result the efficiency of antigen presentation to a dendritic cell. Linkers may include SSVSPTTSVHPTPTSVPPTPTKSSP (SEQ ID NO : 1); PTSTPADSSTITPTATPTATPTIKG (SEQ ID NO :2); TVTPTATATPSAIVTTITPTATTKP (SEQ ID NO :3); or TNGSITVAATAPTVTPTVNATPSAA (SEQ ID NO :4). These examples and others are discussed in WO 2010/104747, the contents of which are incorporated herein by reference. Additional linkers useful for this purpose are described in US 2010/291082, the contents of which are incorporated herein by reference.

[00179] In certain aspects antibody domains, adjuvants antigens or peptide linkers may be bound by high-affinity interacting protein domains. In some embodiments a high-affinity interacting protein domains involves a cohesin-dockerin binding pair. A cohesin-dockerin binding pair may be recombinantly fused to an antibody domain, adjuvants, antigens or peptide linkers. In some aspects the Dockerin is modified such that it is capable of binding to a cohesin domain when recombinantly encoded in an internal (non carboxy or non- amino terminal end) portion of a polypeptide. In certain aspects the linker region is not a peptide linker. An example of a non-peptide linker region may result as the product of chemical conjugation wherein the covalent bond that is formed between molecules is not a peptide bond.

Adjuvants

[00180] In other embodiments an immune adjuvant is directly fused or otherwise linked to the dendritic cell specific antibody in order to enhance the efficacy of the vaccine. In certain aspects the immune adjuvant may be a toll-like receptor (TLR) agonist. TLR agonists comprise flagellins from Salmonella enterica or Vibrio cholerae. In certain aspects the adjuvant is Flagellin-1 or Flagellin-2. TLR agonists may be specific for certain TLR classes (i.e., TLR5, TLR7 or TLR9 agonists) and may be presented in any combination or as any modification. Examples of such immune adjuvants are described in WO 2012/021834, the contents of which are incorporated herein by reference. Poly ICLC, a TLR3 ligand is also contemplated for use with Influenza DC targeting vaccine compositions. In some embodiments the DC targeting vaccine comprises an HA or NP antigen and Poly ICLC is delivered separately from the antibody antigen fusion polypeptide. Interleukins are also contemplated as adjuvants that may be fused to a dendritic cell specific antibody or to a protein domain capable of binding with high affinity to a corresponding or complementary domain on a dendritic cell specific antibody. Non-limiting examples of such interleukins are IL-21, IL-2, IL-9 and IL-10. In some embodiments the interleukin proteins are human interleukins. In certain aspects the adjuvant is an HLA-DR antigen-associated invariant chain that augments antigen processing. In certain aspects the adjuvant is interferon alpha. In yet other embodiments the adjuvant is a toxin that will deliver a death signal to cells also receiving an influenza antigen, thereby augmenting vaccine efficiency. One example of such a toxin is PE38. Any adjuvant may be delivered in fused or conjugated form with a DC targeting vaccine or may be delivered concomitantly as part of the same composition or preparation without fusion or direct conjugation.

Constructs

[00181] The sequences given below, when presented as antibody H or L chain or protein secreted by mammalian cells are shown as amino acids without signal peptide (i.e., as 'mature' secreted protein), while the DNA sequences are the entire coding region including signal sequences if present.

[00182] The example of Ecoli-pET28[CthermoCohesin-FluNP-5-6xHis] given below is for production of the antigen component in an Ecoli expression system and delivery with DC-targeting vehicles carrying a dockerin element either on the H chain, L chain or both.

[00183] All other examples are DC-targeting antibody H chains with C- terminal fusions of various combinations of flexible linker sequences (for enhanced production, note that Flexx varl/2 are novel Flex sequences previously not described), FluNP (either HI sequence or H5 sequence), other antigenic Influenza elements (M2e), and dockerin domains (doc Var2 is used in non-c-terminal or internal fusion sites, while doc varl is used as a C-terminal fusion).

[00184] All examples of H chain constructs are typically used in co- transfection of CHO cells with matching L chain vectors. Also, in some embodiments vaccines will have humanized variable regions, which have been described for anti-CD40 12E12, anti-Langerin 15B10, anti-DCIR 9E8, and anti-LOX-1 15C4.

Ecoli-pET28[CthermoCohesin-FluNP-5-6xHis] [NP-5 shown in double underline; Cohesin shown in single underline]

MDLDAVRI VDTVNAKPGDTVNIPVRFSGIPS GIANCDFVYSYDPNVLEIIEI PGEL IVDPNPT SFDTAVYPDRKMIVFLFAEDSGTGAYAITKDGVFATIVAKVKEGAPNGLS VI FVEVGGFANNDLVEQ TQFFDGGVNVGDTTEPATPTTPVTTPTTTDDLDAASM ASOGTKRSYEOMETGGERONATEIRASVGRMVSGIGRFYIOMCTELKLSDYEGRLIO NSITIERMVLSAFDERRNRYLEEHPSAGKDPKKTGGPIYRRRDGKWVRELILYDKEEI RRIWROANNGEDATAGLTHLMIWHSNLNDATYORTRALVRTGMDPRMCSLMOGST LPRRSGAAGAAVKGVGTMVMELIRMIKRGINDRNFWRGENGRRTRIAYERMCNILK GKFOTAAQRAMMDOVRESRNPGNAEIEDLIFLARSALILRGSVAHKSCLPACVYGLA VASGYDFEREGYSLVGIDPFRLLONSOVFSLIRPNENPAHKSOLVWMACHSAAFEDL RVSSFIRGTRVVPRGOLSTRGVOIASNENMEAMDSNTLELRSRYWAIRTRSGGNTNO ORASAGOISVOPTFSVORNLPFERATIMAAFTGNTEGRTSDMRTEIIRMMESARPEDV SFOGRGVFELSDEKATNPIVPSFDM NEGSYFFGDNAEEYDNHHHHHHfSEO ID NO :5)

ATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGA GACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCA AACTGTGACTTTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAA AACCGGGAGAATTGATAGTTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGT ATATCCTGACAGAAAGATGATAGTATTCCTGTTTGCGGAAGACAGCGGAACAGG AGCGTATGCAATAACTAAAGACGGAGTATTTGCTACGATAGTAGCGAAAGTAAA AGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAAGTAGGCGGATT TGCGAACAATGACCTTGTAGAAC AG AAG AC AC AGTTCTTTGACGGTGGAGTAAA TGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGAC AACAACAGATGATCTGGATGCAGCTAGCATGGCGTCTCAAGGCACCAAACGATC TTATGAACAGATGGAAACTGGTGGGGAACGCCAGAATGCTACTGAGATCAGGGC ATCTGTTGGAAGAATGGTTAGTGGCATTGGGAGGTTCTACATACAGATGTGCACA GAACTCAAACTCAGTGACTATGAAGGGAGGCTGATCC AGAAC AGC ATAACAATA GAGAGAATGGTACTCTCTGCATTTGATGAAAGAAGGAACAGATACCTGGAAGAA CACCCCAGTGCGGGAAAGGACCCGAAGAAGACTGGAGGTCCAATTTATCGGAGG AGAGACGGGAAATGGGTGAGAGAGCTAATTCTGTACGACAAAGAGGAGATCAG GAGGATTTGGCGTCAAGCGAACAATGGAGAGGACGCAACTGCTGGTCTTACCCA CCTGATGATATGGCATTCCAATCTAAATGATGCCACATATCAGAGAACGAGAGCT CTCGTGCGTACTGGAATGGACCCAAGGATGTGCTCTCTGATGCAAGGGTCAACTC TCCCGAGGAGATCTGGAGCTGCCGGTGCAGCAGTAAAGGGGGTAGGGACAATGG TGATGGAGCTGATTCGGATGATAAAACGAGGGATCAACGACCGGAATTTCTGGA GAGGCGAAAATGGAAGAAGAACAAGGATTGCATATGAGAGAATGTGCAACATC CTCAAAGGGAAATTCCAAACAGCAGCACAAAGAGCAATGATGGATCAAGTGCGA GAGAGCAGAAATCCTGGGAATGCTGAAATTGAAGATCTCATTTTTCTGGCACGGT

CTGCACTCATCCTGAGAGGATCAGTGGCCCATAAGTCCTGCTTGCCTGCTTGTGT

GTACGGACTTGCAGTGGCCAGTGGATATGACTTTGAGAGAGAAGGGTACTCTCT

GGTTGGAATAGATCCTTTCCGCCTGCTTCAAAACAGCCAGGTCTTTAGTCTCATT

AGACCAAATGAGAATCCAGCACATAAGAGTCAATTAGTGTGGATGGCATGCCAC

TCTGCAGCATTTGAGGACCTTAGAGTCTCAAGTTTCATCAGAGGGACAAGAGTGG

TCCCAAGAGGACAGCTATCCACCAGAGGGGTTCAAATTGCTTCAAATGAGAACA

TGGAGGCAATGGACTCCAACACTCTTGAACTGAGAAGCAGATATTGGGCTATAA

GAACCAGAAGCGGAGGAAACACCAACCAGCAGAGGGCATCTGCAGGACAGATC

AGCGTTCAGCCCACTTTCTCGGTCCAGAGAAACCTTCCCTTYGAAAGAGCGACCA

TTATGGCAGCATTTACAGGAAATACTGAGGGCAGAACGTCTGACATGAGGACTG

AAATCATAAGAATGATGGAAAGTGCCAGACCAGAAGATGTGTCATTCCAGGGGC

GGGGAGTCTTCGAGCTCTCGGACGAAAAGGCAACGAACCCGATCGTGCCTTCCTT

TGACATGAATAATGAAGGATCTTATTTCTTCGGAGACAATGCAGAGGAGTATGA

CAATCACCATCACCATCACCATTAA(SEQ ID NO :6)

[mAnti-LOX-115C4H-LV-hIgG4H-FluNP-5-6xHis]

EIQLQQTGPELVKPGASVKISCKASGYPFTDYIMVWVKQSHGKSLEWIGNISPYYGTT

NYNLKFKGKATLTVD SSSTAYMQLNSLTSEDSAVYYCARSPNWDGAWFAHWGQ

GALVTVSAAKTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSG

VHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDH PSNTKVDKRVESKYGPPC

PPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE

VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE TISKAK

GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV

LDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKASMASQ

GTKRSYEQMETGGERQNATEIRASVGRiVlVSGiGRFYIQMCTELKLSDYEGRLTQN SlT

IERMVLSAFDERRNRYLEEHPSAGKDP TGGPIYRRRDGKWVR l I .I I YDKF.FIRRI

W RO \NN( il DA 1 \GLTI 1LMIWI ISNLNDA TYQRTRALVRTG DPRMCSLMQGS TLP

RRSGAAGAAVKGVGI VMELIRMIKRGINDRNFWRGENGRRTRIAYERMCNILKG

KFQTAAQRAMMDQVRESRNPGNAEIEDLIFLARSALILRGSVAHKSCLPACVYGLAV

ASGYDFE I :( i ^■ LVGlD FRLLQ SQVFSLIRPNENPAIlKSQLVWMACHSAy\FEDLR

VSSFIRGTRVVPRGQLSTRGVQIASNENMEAMDSNTLELRS

RASAGQlSVQP rFSVQRNLPFERATIMAAFTGNTEGRTSDMRTM R MESARPEDVS FQGRCrVFELSDEKATOPI VPSFDMN EGS YFFGDN AEEYD I IHH HHH(SEQ ID NO :7)

ATGGGAGGGATCTGGATCTTTCTCTTCCTCCTGTCAGGAACTGCAGGTGCCCACT CTGAGATCCAGCTGCAGCAGACTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAG TGAAGATATCCTGCAAGGCTTCTGGTTATCCATTCACTGACTACATCATGGTCTG GGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGAAATATTAGTCCTTA CTATGGTACTACTAACTACAATCTGAAGTTCAAGGGCAAGGCCACATTGACTGTA GACAAATCTTCCAGCACAGCCTACATGCAGCTCAACAGTCTGACATCTGAGGACT CTGCAGTCTATTACTGTGCAAGATCCCCTAACTGGGACGGGGCCTGGTTTGCTCA CTGGGGCCAAGGGGCTCTGGTCACTGTCTCTGCAGCCAAAACAAAGGGCCCATC CGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTG GGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAG GCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACT CTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACC TACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTT GAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGGGG GACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCG GACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGT CCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCC GCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCT GCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGG CCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA GCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGT CAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGG GAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGC AGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTA CACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGCATGGCGTCTCAAGGC ACCAAACGATCTTATGAACAGATGGAAACTGGTGGGGAACGCCAGAATGCTACT GAGATCAGGGCATCTGTTGGAAGAATGGTTAGTGGCATTGGGAGGTTCTACATA CAGATGTGCACAGAACTCAAACTCAGTGACTATGAAGGGAGGCTGATCCAGAAC AGCATAACAATAGAGAGAATGGTACTCTCTGCATTTGATGAAAGAAGGAACAGA TACCTGGAAGAACACCCCAGTGCGGGAAAGGACCCGAAGAAGACTGGAGGTCC AATTTATCGGAGGAGAGACGGGAAATGGGTGAGAGAGCTAATTCTGTACGACAA AGAGGAGATCAGGAGGATTTGGCGTCAAGCGAACAATGGAGAGGACGCAACTG CTGGTCTTACCCACCTGATGATATGGCATTCCAATCTAAATGATGCCACATATCA GAGAACGAGAGCTCTCGTGCGTACTGGAATGGACCCAAGGATGTGCTCTCTGAT GCAAGGGTCAACTCTCCCGAGGAGATCTGGAGCTGCCGGTGCAGCAGTAAAGGG GGTAGGGACAATGGTGATGGAGCTGATTCGGATGATAAAACGAGGGATCAACGA CCGGAATTTCTGGAGAGGCGAAAATGGAAGAAGAACAAGGATTGCATATGAGA GAATGTGCAACATCCTCAAAGGGAAATTCCAAACAGCAGCACAAAGAGCAATGA TGGATCAAGTGCGAGAGAGCAGAAATCCTGGGAATGCTGAAATTGAAGATCTCA TTTTTCTGGCACGGTCTGCACTCATCCTGAGAGGATCAGTGGCCCATAAGTCCTG CTTGCCTGCTTGTGTGTACGGACTTGCAGTGGCCAGTGGATATGACTTTGAGAGA GAAGGGTACTCTCTGGTTGGAATAGATCCTTTCCGCCTGCTTCAAAACAGCCAGG TCTTTAGTCTCATTAGACCAAATGAGAATCCAGCACATAAGAGTCAATTAGTGTG GATGGCATGCCACTCTGCAGCATTTGAGGACCTTAGAGTCTCAAGTTTCATCAGA GGGACAAGAGTGGTCCCAAGAGGACAGCTATCCACCAGAGGGGTTCAAATTGCT TCAAATGAGAACATGGAGGCAATGGACTCCAACACTCTTGAACTGAGAAGCAGA TATTGGGCTATAAGAACCAGAAGCGGAGGAAACACCAACCAGCAGAGGGCATCT GC AGGAC AGATCAGCGTTC AGCCC ACTTTCTCGGTCC AGAGAAACCTTCCCTTTG AAAGAGCGACCATTATGGCAGCATTTACAGGAAATACTGAGGGCAGAACGTCTG ACATGAGGACTGAAATCATAAGAATGATGGAAAGTGCCAGACCAGAAGATGTGT CATTCCAGGGGCGGGGAGTCTTCGAGCTCTCGGACGAAAAGGCAACGAACCCGA TCGTGCCTTCCTTTGACATGAATAATGAAGGATCTTATTTCTTCGGAGACAATGC AGAGGAGTATGACAATCACCATCACCATCACCATTAA(SEQ ID NO :8)

[mAnti-LOX-115C4H-LV-hIgG4H-C-Dockerin-v2-FluNP-5-6xHis] [NP-5 shown in double underline; Dockerin-v2 shown in single underline]

EIQLQQTGPELVKPGASVKISCKASGYPFTDYIMVWVKQSHGKSLEWIGNISPYYGTT NYNLKFKGKATLTVDKSSSTAYMQLNSLTSEDSAVYYCARSPNWDGAWFAHWGQ GALVTVSAAKTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPC PPCPAPEFEGGPSVFLFPP PKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSRLTVDKSRWQEGNVFSCSV HEALHNHYTQKSLSLSLGKASSEDTO PPAPTLIGDVNADGKIDSTDLTLLKRYLLRSATLTEEKILNADTDGNGTVNSTDLNYL KKYILRVISVFPAEGNKPPTPTPTKTPVATPSPTQPLFTPSFKDVTASMASOGTKRSYE OMETGGERONATEIRASVGRMVSG1GRFYIOMCTELKLSDYEGRLIONSITIERMVLS AFDERRNRYLEEHPSAGKDPKKTGGPIYRRRDGKWVRELILYDKEEIRRIWROANNG EDATAGLTHLMIWHSNLNDATYORTRALVRTGMDPRMCSLMOGSTLPRRSGAAGA AVKGVGTMVMELIRMI RGINDRNFWRGENGRRTRIAYERMCNILKGKFOTAAORA MMDOVRESRNPGNAEIEDLIFLARSALILRGSVAHKSCLPACVYGLAVASGYDFERE GYSLVGIDPFRLLONSOVFSLIRPNENPAHKSOLVWVACHSAAFEDLRVSSFIRGTRV VPRGOLSTRGVOIASNENMEAMDSNTLELRSRYWAIRTRSGGNTNOORASAGOISV OPTFSVORNLPFERATIMAAFTGNTEGRTSDMRTEIIRMMESARPEDVSFOGRGVFEL SDEKATNPIVPSFDMNNEGSYFFGDNAEEYDNHHHHHHCSEO ID NO :9)

ATGGGAGGGATCTGGATCTTTCTCTTCCTCCTGTCAGGAACTGCAGGTGCCCACT CTGAGATCCAGCTGCAGCAGACTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAG TGAAGATATCCTGCAAGGCTTCTGGTTATCCATTCACTGACTACATCATGGTCTG GGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGAAATATTAGTCCTTA CTATGGTACTACTAACTACAATCTGAAGTTCAAGGGCAAGGCCACATTGACTGTA GACAAATCTTCCAGCACAGCCTACATGCAGCTCAACAGTCTGACATCTGAGGACT CTGCAGTCTATTACTGTGCAAGATCCCCTAACTGGGACGGGGCCTGGTTTGCTCA CTGGGGCCAAGGGGCTCTGGTCACTGTCTCTGCAGCCAAAACAAAGGGCCCATC CGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTG GGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAG GCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACT CTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACC TACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTT GAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGGGG GACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCG GACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGT CCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCC GCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCT GCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGG CCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA GCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGT C AGCCTGACCTGCCTGGTC AAAGGCTTCTACCCC AGCGACATCGCCGTGGAGTGG GAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGC AGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTA CACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGTAGCGAGGATACTCA ACCACCTGCACCGACACTCATAGGTGATGTAAATGCCGATGGAAAGATTGACTCT ACAGACCTTACATTATTAAAAAGGTATTTGCTAAGAAGTGCAACGCTCACAGAA GAGAAAATTTTAAATGCGGATACAGACGGAAACGGCACGGTTAATTCAACTGAC TTAAATTATCTGAAAAAATACATATTAAGGGTTATATCTGTATTTCCGGCAGAGG GCAATAAGCCCCCGACTCCGACTCCAACAAAAACACCTGTGGCAACTCCGTCAC CAACACAACCACTGTTTACACCCAGCTTTAAAGATGTAACGGCTAGCATGGCGTC TCAAGGCACCAAACGATCTTATGAACAGATGGAAACTGGTGGGGAACGCCAGAA TGCTACTGAGATCAGGGCATCTGTTGGAAGAATGGTTAGTGGCATTGGGAGGTTC TACATACAGATGTGCACAGAACTCAAACTCAGTGACTATGAAGGGAGGCTGATC CAGAACAGCATAACAATAGAGAGAATGGTACTCTCTGCATTTGATGAAAGAAGG AACAGATACCTGGAAGAACACCCCAGTGCGGGAAAGGACCCGAAGAAGACTGG AGGTCCAATTTATCGGAGGAGAGACGGGAAATGGGTGAGAGAGCTAATTCTGTA CGACAAAGAGGAGATCAGGAGGATTTGGCGTCAAGCGAACAATGGAGAGGACG CAACTGCTGGTCTTACCCACCTGATGATATGGCATTCCAATCTAAATGATGCCAC ATATCAGAGAACGAGAGCTCTCGTGCGTACTGGAATGGACCCAAGGATGTGCTC TCTGATGCAAGGGTCAACTCTCCCGAGGAGATCTGGAGCTGCCGGTGCAGCAGT AAAGGGGGTAGGGACAATGGTGATGGAGCTGATTCGGATGATAAAACGAGGGA TCAACGACCGGAATTTCTGGAGAGGCGAAAATGGAAGAAGAACAAGGATTGCGT ATGAGAGAATGTGCAACATCCTCAAAGGGAAATTCCAAACAGCAGCACAAAGAG CAATGATGGATCAAGTGCGAGAGAGCAGAAATCCTGGGAATGCTGAAATTGAAG ATCTCATTTTTCTGGCACGGTCTGCACTCATCCTGAGAGGATCAGTGGCCCATAA GTCCTGCTTGCCTGCTTGTGTGTACGGACTTGCAGTGGCCAGTGGATATGACTTT GAGAGAGAAGGGTACTCTCTGGTTGGAATAGATCCTTTCCGCCTGCTTCAAAACA GCCAGGTCTTTAGTCTCATTAGACCAAATGAGAATCCAGCACATAAGAGTCAATT AGTGTGGGTGGCATGCCACTCTGCAGCATTTGAGGACCTTAGAGTCTCAAGTTTC ATCAGAGGGACAAGAGTGGTCCCAAGAGGACAGCTATCCACCAGAGGGGTTCAA ATTGCTTCAAATGAGAACATGGAGGCAATGGACTCCAACACTCTTGAACTGAGA AGCAGATATTGGGCTATAAGAACCAGAAGCGGAGGAAACACCAACCAGCAGAG GGCATCTGCAGGACAGATCAGCGTTCAGCCCACTTTCTCGGTCCAGAGAAACCTT CCCTTTGAAAGAGCGACCATTATGGCAGCATTTACAGGAAATACTGAGGGCAGA ACGTCTGACATGAGGACTGAAATCATAAGAATGATGGAAAGTGCCAGACCAGAA GATGTGTCATTCCAGGGGCGGGGAGTCTTCGAGCTCTCGGACGAAAAGGCAACG AACCCGATCGTGCCTTCCTTTGACATGAATAATGAAGGATCTTATTTCTTCGGAG ACAATGCAGAGGAGTATGACAATCACCATCACCATCACCATTAA(SEQ ID NO :10) [manti-CD40_12E12.3F3_H-LV-hIgG4H-C-FluNP-5-6xHis] [NP-5 shown in double underline]

EVKLVESGGGLVQPGGSL LSCATSGFTFSDYYMYWVRQTPEKRLEWVAYINSGGG

STYYPDTVKGRFTISRDNAKNTLYLQMSRLKSEDTAMYYCARRGLPFHAMDYWGQ

GTSVTVSSAKTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSG V HTFP A VLQ S S GL YS LS S V VTVP S S SLGTKTYTCNVDH PSNTKVDKRVESKYGPPCPP CPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQ PREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY TTPPVLD SDGSFFLYSRLTVDKSRWOEGNVFSCSVMHEALHNHYTOKSLSLSLGKASMASOGT KRSYEOMETGGERONATEIRASVGRMVSGIGRFYIOMCTELKLSDYEGRLIONSITIE RMVLSAFDERRNRYLEEHPSAGKDPK TGGPIYRRRDGKWVRELILYDKEEIRRIWR OANNGEDATAGLTHLMIWHSNLNDATYORTRALVRTGMDPRMCSLMOGSTLPRRS GAAGAAVKGVGTMVMELIRMIKRGINDRNFWRGENGRRTRIAYERMCNILKG FO TAAORAMMDOVRESRNPGNAEIEDLIFLARSALILRGSVAHKSCLPACVYGLAVASG YDFEREGYSLVGIDPFRLLONSOVFSLIRPNENPAHKSOLVWMACHSAAFEDLRVSSF IRGTRVVPRGOLSTRGVOIASNENMEAMDSNTLELRSRYWAIRTRSGGNTNOORAS AGOISVOPTFSVORNLPFERATIMAAFTGNTEGRTSDMRTEIIRMMESARPEDVSFOG RGVFELSDEKATNPIVPSFDMNNEGSYFFGDNAEEYDNHHHHHHiSEO ID NO : 1 1 ) ATGAACTTGGGGCTCAGCTTGATTTTCCTTGTCCTTGTTTTAAAAGGTGTCCAGTG TGAAGTGAAGCTGGTGGAGTCTGGGGGAGGCTTAGTGCAGCCCGGAGGGTCCCT GAAACTCTCCTGTGCAACCTCTGGATTCACTTTCAGTGACTATTACATGTATTGGG TTCGCCAGACTCCAGAGAAGAGGCTGGAGTGGGTCGCATACATTAATTCTGGTG GTGGTAGCACCTATTATCCAGACACTGTAAAGGGCCGATTCACCATCTCCAGAGA CAATGCCAAGAACACCCTGTACCTGCAAATGAGCCGGCTGAAGTCTGAGGACAC AGCCATGTATTACTGTGCAAGACGGGGGTTACCGTTCCATGCTATGGACTATTGG GGTCAAGGAACCTCAGTCACCGTCTCCTCAGCCAAAACGAAGGGCCCATCCGTCT TCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCC CTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACT CCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACA CCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGT CCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGGGGGACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAG TTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGG GAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACC AGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCC CGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCAC AGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCC TGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCG ACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGG AGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACAC ACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGCATGGCGTCTCAAGGCACC AAACGATCTTATGAACAGATGGAAACTGGTGGGGAACGCCAGAATGCTACTGAG ATCAGGGCATCTGTTGGAAGAATGGTTAGTGGCATTGGGAGGTTCTACATACAG ATGTGCACAGAACTCAAACTCAGTGACTATGAAGGGAGGCTGATCCAGAACAGC ATAACAATAGAGAGAATGGTACTCTCTGCATTTGATGAAAGAAGGAACAGATAC CTGGAAGAACACCCCAGTGCGGGAAAGGACCCGAAGAAGACTGGAGGTCCAATT TATCGGAGGAGAGACGGGAAATGGGTGAGAGAGCTAATTCTGTACGACAAAGA GGAGATCAGGAGGATTTGGCGTCAAGCGAACAATGGAGAGGACGCAACTGCTGG TCTTACCCACCTGATGATATGGCATTCCAATCTAAATGATGCCACATATCAGAGA ACGAGAGCTCTCGTGCGTACTGGAATGGACCCAAGGATGTGCTCTCTGATGCAA GGGTCAACTCTCCCGAGGAGATCTGGAGCTGCCGGTGCAGCAGTAAAGGGGGTA GGGACAATGGTGATGGAGCTGATTCGGATGATAAAACGAGGGATCAACGACCGG AATTTCTGGAGAGGCGAAAATGGAAGAAGAACAAGGATTGCATATGAGAGAAT GTGCAACATCCTCAAAGGGAAATTCCAAACAGCAGCACAAAGAGCAATGATGGA TCAAGTGCGAGAGAGCAGAAATCCTGGGAATGCTGAAATTGAAGATCTCATTTTT CTGGCACGGTCTGCACTC ATCCTGAGAGGATC AGTGGCCCATAAGTCCTGCTTGC CTGCTTGTGTGTACGGACTTGCAGTGGCCAGTGGATATGACTTTGAGAGAGAAGG GTACTCTCTGGTTGGAATAGATCCTTTCCGCCTGCTTCAAAACAGCCAGGTCTTTA GTCTCATTAGACCAAATGAGAATCCAGCACATAAGAGTCAATTAGTGTGGATGG CATGCCACTCTGCAGCATTTGAGGACCTTAGAGTCTCAAGTTTCATCAGAGGGAC AAGAGTGGTCCCAAGAGGACAGCTATCCACCAGAGGGGTTCAAATTGCTTCAAA TGAGAACATGGAGGCAATGGACTCCAACACTCTTGAACTGAGAAGCAGATATTG GGCTATAAGAACCAGAAGCGGAGGAAACACCAACCAGCAGAGGGCATCTGCAG GACAGATCAGCGTTCAGCCCACTTTCTCGGTCCAGAGAAACCTTCCCTTTGAAAG AGCGACCATTATGGCAGCATTTACAGGAAATACTGAGGGCAGAACGTCTGACAT GAGGACTGAAATCATAAGAATGATGGAAAGTGCCAGACCAGAAGATGTGTCATT CCAGGGGCGGGGAGTCTTCGAGCTCTCGGACGAAAAGGCAACGAACCCGATCGT GCCTTCCTTTGACATGAATAATGAAGGATCTTATTTCTTCGGAGACAATGCAGAG GAGTATGACAATCACCATCACCATCACCATTAA(SEQ ID NO : 12) [manti-CD40_12E12.3F3_H-LV-hIgG4H-C-Dockerin-v2-FluNP-5-6xHi s] [NP-5 shown in double underline; Dockerin-v2 shown in single underline]

EVKLVESGGGLVQPGGSLKLSCATSGFTFSDYYMYWVRQTPEKRLEWVAYINSGGG STYYPDTVKGRFTISRDNAKNTLYLQMSRLKSEDTAMYYCARRGLPFHAMDYWGQ GTSVTVSSAKTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVES YGPPCPP CPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE TISKAKGQ PREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKASSEDTQPP APTLIGDVNADGKIDSTDLTLLKRYLLRSATLTEEKILNADTDGNGTVNSTDLNYLK KYILRVISVFPAEGN PPTPTPTKTPVATPSPTQPLFTPSFKDVTASMASOGTKRSYEO METGGERONATEIRASVGRMVSGIGRFYIOMCTELKLSDYEGRLIONSITIERMVLSA FDERRNRYLEEHPSAGKDPKKTGGPIYRRRDG WVRELILYDKEEIRRIWROANNGE DATAGLTHLMIWHSNLNDATYORTRALVRTGMDPRMCSLMOGSTLPRRSGAAGAA VKGVGTMVMELIRMIKRGINDRNFWRGENGRRTRIAYERMCNILKGKFOTAAORA MMDOVRESRNPGNAEIEDLIFLARSALILRGSVAHKSCLPACVYGLAVASGYDFERE GYSLVGIDPFRLLONSOVFSLIRPNENPAHKSOLVWVACHSAAFEDLRVSSFIRGTRV VPRGOLSTRGVOIASNENMEAMDSNTLELRSRYWAIRTRSGGNTNOORASAGOISV OPTFSVORNLPFERATIMAAFTGNTEGRTSDMRTEIIRMMESARPEDVSFOGRGVFEL SDEKATNPIVPSFDMNNEGSYFFGDNAEEYDNHHHHHHiSEO ID NO : 13)

ATGAACTTGGGGCTCAGCTTGATTTTCCTTGTCCTTGTTTTAAAAGGTGTCCAGTG TGAAGTGAAGCTGGTGGAGTCTGGGGGAGGCTTAGTGCAGCCCGGAGGGTCCCT GAAACTCTCCTGTGCAACCTCTGGATTCACTTTCAGTGACTATTACATGTATTGGG TTCGCCAGACTCCAGAGAAGAGGCTGGAGTGGGTCGCATACATTAATTCTGGTG GTGGTAGCACCTATTATCCAGACACTGTAAAGGGCCGATTCACCATCTCCAGAGA CAATGCCAAGAACACCCTGTACCTGCAAATGAGCCGGCTGAAGTCTGAGGACAC AGCCATGTATTACTGTGCAAGACGGGGGTTACCGTTCCATGCTATGGACTATTGG GGTCAAGGAACCTCAGTCACCGTCTCCTCAGCCAAAACGAAGGGCCCATCCGTCT TCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCC CTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACT CCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACA CCTGCAACGTAGATCAC AAGCCC AGC AACACCAAGGTGGACAAGAGAGTTG AGT CCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGGGGGACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAG TTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGG GAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACC AGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCC CGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCAC AGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCC TGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCG ACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGG AGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACAC ACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGTAGCGAGGATACTCAACC ACCTGCACCGACACTCATAGGTGATGTAAATGCCGATGGAAAGATTGACTCTAC AGACCTTACATTATTAAAAAGGTATTTGCTAAGAAGTGCAACGCTCACAGAAGA GAAAATTTTAAATGCGGATACAGACGGAAACGGCACGGTTAATTCAACTGACTT AAATTATCTGAAAAAATACATATTAAGGGTTATATCTGTATTTCCGGCAGAGGGC AATAAGCCCCCGACTCCGACTCCAACAAAAACACCTGTGGCAACTCCGTCACCA ACACAACCACTGTTTACACCCAGCTTTAAAGATGTAACGGCTAGCATGGCGTCTC AAGGCACCAAACGATCTTATGAACAGATGGAAACTGGTGGGGAACGCCAGAATG CTACTGAGATCAGGGCATCTGTTGGAAGAATGGTTAGTGGCATTGGGAGGTTCTA CATACAGATGTGCACAGAACTCAAACTCAGTGACTATGAAGGGAGGCTGATCCA GAACAGCATAACAATAGAGAGAATGGTACTCTCTGCATTTGATGAAAGAAGGAA CAGATACCTGGAAGAACACCCCAGTGCGGGAAAGGACCCGAAGAAGACTGGAG GTCCAATTTATCGGAGGAGAGACGGGAAATGGGTGAGAGAGCTAATTCTGTACG ACAAAGAGGAGATCAGGAGGATTTGGCGTCAAGCGAACAATGGAGAGGACGCA ACTGCTGGTCTTACCCACCTGATGATATGGCATTCCAATCTAAATGATGCCACAT ATCAGAGAACGAGAGCTCTCGTGCGTACTGGAATGGACCCAAGGATGTGCTCTC TGATGCAAGGGTCAACTCTCCCGAGGAGATCTGGAGCTGCCGGTGCAGCAGTAA AGGGGGTAGGGACAATGGTGATGGAGCTGATTCGGATGATAAAACGAGGGATCA ACGACCGGAATTTCTGGAGAGGCGAAAATGGAAGAAGAACAAGGATTGCGTATG AGAGAATGTGCAACATCCTCAAAGGGAAATTCCAAACAGCAGCACAAAGAGCA ATGATGGATCAAGTGCGAGAGAGCAGAAATCCTGGGAATGCTGAAATTGAAGAT CTCATTTTTCTGGCACGGTCTGCACTCATCCTGAGAGGATCAGTGGCCCATAAGT CCTGCTTGCCTGCTTGTGTGTACGGACTTGCAGTGGCCAGTGGATATGACTTTGA GAGAGAAGGGTACTCTCTGGTTGGAATAGATCCTTTCCGCCTGCTTCAAAACAGC CAGGTCTTTAGTCTCATTAGACCAAATGAGAATCCAGCACATAAGAGTCAATTAG TGTGGGTGGCATGCCACTCTGCAGCATTTGAGGACCTTAGAGTCTCAAGTTTCAT CAGAGGGACAAGAGTGGTCCCAAGAGGACAGCTATCCACCAGAGGGGTTCAAAT TGCTTCAAATGAGAACATGGAGGCAATGGACTCCAACACTCTTGAACTGAGAAG CAGATATTGGGCTATAAGAACCAGAAGCGGAGGAAACACCAACCAGCAGAGGG CATCTGCAGGACAGATCAGCGTTCAGCCCACTTTCTCGGTCCAGAGAAACCTTCC CTTTGAAAGAGCGACCATTATGGCAGCATTTACAGGAAATACTGAGGGCAGAAC GTCTGACATGAGGACTGAAATCATAAGAATGATGGAAAGTGCCAGACCAGAAGA TGTGTCATTCCAGGGGCGGGGAGTCTTCGAGCTCTCGGACGAAAAGGCAACGAA CCCGATCGTGCCTTCCTTTGACATGAATAATGAAGGATCTTATTTCTTCGGAGAC AATGCAGAGGAGTATGACAATCACCATCACCATCACCATTAA(SEQ ID NO : 14)

[mAnti-DCIR_9E8_H-LV-hIgG4H-C-FluNP-5-6xHis] [NP-5 shown in double underline] QVTLKESGPGILQPSQTLSLTCSFSGFSLSTSGMGLSWIRQPSGKGLEWLAHIYWDDD RYNPSL SRLTISKDTSSNQVFLKITIVDTADAATYYCARSSHYYGYGYGGYFDVW GAGTTVTVSSAKTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDH PSNTKVDKRVESKYGPP CPPCPAPEFEGGPSVFLFPP PKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKT PREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSN GLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKASMASQ GTKRSYEOMETGGERONATEIRASVGRMVSGIGRFYIOMCTELKLSDYEGRLIONSIT IERMVLSAFDERRNRYLEEHPSAGKDPKKTGGPIYRRRDGKWVRELILYDKEEIRRI WROANNGEDATAGLTHLMIWHSNLNDATYORTRALVRTGMDPRMCSLMOGSTLP RRSGAAGAAVKGVGTMVMELIRMIKRGINDRNFWRGENGRRTRIAYERMCNILKG KFOTAAORAMMDOVRESRNPGNAEIEDLIFLARSALILRGSVAHKSCLPACVYGLAV ASGYDFEREGYSLVGIDPFRLLONSOVFSLIRPNENPAH SOLVWMACHSAAFEDLR VSSFIRGTRVVPRGOLSTRGVOIASNENMEAMDSNTLELRSRYWAIRTRSGGNTNOO RASAGOISVOPTFSVORNLPFERATIMAAFTGNTEGRTSDMRTEIIRMMESARPEDVS FOGRGVFELSDEKATNPIVPSFDMNNEGSYFFGDNAEEYDNHHHHHHCSEO ID NO : 15)

ATGAACAGGCTTACTTCCTCATTGCTGCTGCTGATTGTCCCTGCATATGTCCTGTC CCAGGTTACTCTGAAAGAGTCTGGCCCTGGGATATTGCAGCCCTCCCAGACCCTC AGTCTGACTTGTTCTTTCTCTGGGTTTTCACTGAGCACTTCTGGTATGGGTCTGAG CTGGATTCGTCAGCCTTCAGGAAAGGGTCTGGAGTGGCTGGCACACATTTACTGG GATGATGACAAGCGCTATAACCCATCCCTGAAGAGCCGGCTCACAATCTCCAAG GATACCTCCAGCAACCAGGTTTTCCTCAAGATCACCATTGTGGACACTGCAGATG CTGCCACATACTACTGTGCTCGAAGCTCCCATTACTACGGTTATGGCTACGGGGG ATACTTCGATGTCTGGGGCGCAGGGACCACGGTCACCGTCTCCTCAGCCAAAACG AAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCA CAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTC GTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAG TCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGG GCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGG ACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGA GTTCGAAGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTC ATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAA GACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCC AAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTC CTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGG CAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACC AAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCC TCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGAC AAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCT CTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGCA TGGCGTCTCAAGGCACCAAACGATCTTATGAACAGATGGAAACTGGTGGGGAAC GCCAGAATGCTACTGAGATCAGGGCATCTGTTGGAAGAATGGTTAGTGGCATTG GGAGGTTCTACATACAGATGTGCACAGAACTCAAACTCAGTGACTATGAAGGGA GGCTGATCCAGAACAGCATAACAATAGAGAGAATGGTACTCTCTGCATTTGATG AAAGAAGGAACAGATACCTGGAAGAACACCCCAGTGCGGGAAAGGACCCGAAG AAGACTGGAGGTCC AATTTATCGGAGGAGAGACGGGAAATGGGTGAGAGAGCT AATTCTGTACGACAAAGAGGAGATCAGGAGGATTTGGCGTCAAGCGAACAATGG AGAGGACGCAACTGCTGGTCTTACCCACCTGATGATATGGCATTCCAATCTAAAT GATGCCACATATCAGAGAACGAGAGCTCTCGTGCGTACTGGAATGGACCCAAGG ATGTGCTCTCTGATGCAAGGGTCAACTCTCCCGAGGAGATCTGGAGCTGCCGGTG CAGCAGTAAAGGGGGTAGGGACAATGGTGATGGAGCTGATTCGGATGATAAAAC GAGGGATCAACGACCGGAATTTCTGGAGAGGCGAAAATGGAAGAAGAACAAGG ATTGCATATGAGAGAATGTGCAACATCCTCAAAGGGAAATTCCAAACAGCAGCA CAAAGAGCAATGATGGATCAAGTGCGAGAGAGCAGAAATCCTGGGAATGCTGA AATTGAAGATCTCATTTTTCTGGCACGGTCTGCACTCATCCTGAGAGGATCAGTG GCCCATAAGTCCTGCTTGCCTGCTTGTGTGTACGGACTTGCAGTGGCCAGTGGAT ATGACTTTGAGAGAGAAGGGTACTCTCTGGTTGGAATAGATCCTTTCCGCCTGCT TCAAAACAGCCAGGTCTTTAGTCTCATTAGACCAAATGAGAATCCAGCACATAA GAGTCAATTAGTGTGGATGGCATGCCACTCTGCAGCATTTGAGGACCTTAGAGTC TCAAGTTTCATCAGAGGGACAAGAGTGGTCCCAAGAGGACAGCTATCCACCAGA GGGGTTCAAATTGCTTCAAATGAGAACATGGAGGCAATGGACTCCAACACTCTT GAACTGAGAAGCAGATATTGGGCTATAAGAACCAGAAGCGGAGGAAACACCAA CCAGCAGAGGGCATCTGCAGGACAGATCAGCGTTCAGCCCACTTTCTCGGTCCAG AGAAACCTTCCCTTTGAAAGAGCGACCATTATGGCAGCATTTACAGGAAATACTG AGGGCAGAACGTCTGACATGAGGACTGAAATCATAAGAATGATGGAAAGTGCCA GACCAGAAGATGTGTCATTCCAGGGGCGGGGAGTCTTCGAGCTCTCGGACGAAA AGGCAACGAACCCGATCGTGCCTTCCTTTGACATGAATAATGAAGGATCTTATTT CTTCGGAGACAATGCAGAGGAGTATGACAATCACCATCACCATCACCATTAA(SE Q ID NO :16) [manti-CD40_12E12.3F3_H-LV-hIgG4H-C-FluNP-5 vl-6xHis] [NP-5 shown in double underline]

EVKLVESGGGLVQPGGSLKLSCATSGFTFSDYYMYWVRQTPEKRLEWVAYINSGGG

STYYPDTVKGRFTISRDNAKNTLYLQMSRLKSEDTAMYYCARRGLPFHAMDYWGQ

GTSVTVSSAKTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSG V HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVES YGPPCPP CPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSN GLPSSIEKTISKAKGQ PREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN YKTTPPVLD SDGSFFLYSRLTVD SRWOEGNVFSCSVMHEALHNHYTOKSLSLSLGKASRSYEOM ETGGERONATEIRASVGRMVSGIGRFYIOMCTELKLSDYEGRLIONSITIERMVLSAF DERRNRYLEEHPSAGKDPKKTGGPIYRRRDGKWVRELILYDKEEIRRIWROANNGED ATAGLTHLMIWHSNLNDATYORTRALVRTGMDPRMCSLMOGSTLPRRSGAAGAAV KGVGTMVMELIRMIKRGINDRNFWRGENGRRTRIAYERMCNILKGKFOTAAORAM MDOVRESRNPGNAEIEDLIFLARSALILRGSVAHKSCLPACVYGLAVASGYDFEREG YSLVGIDPFRLLONSOVFSLIRPNENPAHKSOLVWMACHSAAFEDLRVSSFIRGTRVV PRGOLSTRGVOIASNENMEAMDSNTLELRSRYWAIRTRSGGNTNOORASASAFTGN TEGRTSDMRTEIIRMMESARPEDVSFOGRGVFELSDEKATNPIVPSFDMNNEGSYFFG DNAEEYDNHHHHHHiSEO ID NO : 17) ATGAACTTGGGGCTCAGCTTGATTTTCCTTGTCCTTGTTTTAAAAGGTGTCCAGTG TGAAGTGAAGCTGGTGGAGTCTGGGGGAGGCTTAGTGCAGCCTGGAGGGTCCCT GAAACTCTCCTGTGCAACCTCTGGATTCACTTTCAGTGACTATTACATGTATTGGG TTCGCCAGACTCCAGAGAAGAGGCTGGAGTGGGTCGCATACATTAATTCTGGTG GTGGTAGCACCTATTATCCAGACACTGTAAAGGGCCGATTCACCATCTCCAGAGA C AATGCC AAGAACACCCTGTACCTGCAAATGAGCCGGCTGAAGTCTGAGGAC AC AGCCATGTATTACTGTGCAAGACGGGGGTTACCGTTCCATGCTATGGACTATTGG GGTCAAGGAACCTCAGTCACCGTCTCCTCAGCCAAAACGAAGGGCCCATCCGTCT TCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCC CTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACT CCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACA CCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGT CCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGGGGGACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAG TTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGG GAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACC AGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCC CGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCAC AGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCC TGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCG ACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGG AGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACAC ACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGTCGATCTTATGAACAGATG GAAACTGGTGGGGAACGCCAGAATGCTACTGAGATCAGGGCATCTGTTGGAAGA ATGGTTAGTGGCATTGGGAGGTTCTACATACAGATGTGCACAGAACTCAAACTCA GTGACTATGAAGGGAGGCTGATCCAGAACAGCATAACAATAGAGAGAATGGTAC TCTCTGCATTTGATGAAAGAAGGAACAGATACCTGGAAGAACACCCCAGTGCGG GAAAGGACCCGAAGAAGACTGGAGGTCCAATTTATCGGAGGAGAGACGGGAAA TGGGTGAGAGAGCTAATTCTGTACGACAAAGAGGAGATCAGGAGGATTTGGCGT CAAGCGAACAATGGAGAGGACGCAACTGCTGGTCTTACCCACCTGATGATATGG CATTCCAATCTAAATGATGCCACATATCAGAGAACGAGAGCTCTCGTGCGTACTG GAATGGACCCAAGGATGTGCTCTCTGATGCAAGGGTCAACTCTCCCGAGGAGAT CTGGAGCTGCCGGTGCAGCAGTAAAGGGGGTAGGGACAATGGTGATGGAGCTGA TTCGGATGATAAAACGAGGGATCAACGACCGGAATTTCTGGAGAGGCGAAAATG GAAGAAGAACAAGGATTGCATATGAGAGAATGTGCAACATCCTCAAAGGGAAAT TCCAAACAGCAGCACAAAGAGCAATGATGGATCAAGTGCGAGAGAGCAGAAAT CCTGGGAATGCTGAAATTGAAGATCTCATTTTTCTGGCACGGTCTGCACTCATCC TGAGAGGATCAGTGGCCCATAAGTCCTGCTTGCCTGCTTGTGTGTACGGACTTGC AGTGGCCAGTGGATATGACTTTGAGAGAGAAGGGTACTCTCTGGTTGGAATAGA TCCTTTCCGCCTGCTTCAAAACAGCCAGGTCTTTAGTCTCATTAGACCAAATGAG AATCCAGCACATAAGAGTCAATTAGTGTGGATGGCATGCCACTCTGCAGCATTTG AGGACCTTAGAGTCTCAAGTTTCATCAGAGGGACAAGAGTGGTCCCAAGAGGAC AGCTATCCACCAGAGGGGTTCAAATTGCTTCAAATGAGAACATGGAGGCAATGG ACTCCAACACTCTTGAACTGAGAAGCAGATATTGGGCTATAAGAACCAGAAGCG GAGGAAACACCAACCAGCAGAGGGCATCTGCTAGTGCATTTACAGGAAATACTG AGGGCAGAACGTCTGACATGAGGACTGAAATCATAAGAATGATGGAAAGTGCCA GACCAGAAGATGTGTCATTCCAGGGGCGGGGAGTCTTCGAGCTCTCGGACGAAA AGGC AACGAACCCGATCGTGCCTTCCTTTGACATGAATAATGAAGGATCTTATTT CTTCGGAGACAATGCAGAGGAGTATGACAATCACCATCACCATCACCATTAA(SE Q ID NO : 18) [mAnti-DCIR 9E8_H-LV-hIgG4H-C-Flex-vl-FluNP-5-v2-6xHis] [NP-5 shown in double underline; Flex-vl shown in single underline

QVTLKESGPGILQPSQTLSLTCSFSGFSLSTSGMGLSWIRQPSGKGLEWLAHIYWDDD KRYNPSLKSRLTISKDTSSNQVFLKITIVDTADAATYYCARSSHYYGYGYGGYFDVW GAGTTVTVSSAKTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLGT TYTCNVDHKPSNTKVDKRVESKYGPP CPPCPAPEFEGGPSVFLFPP PKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKASQTPTN TISVTPTNNSTPTNNSNPKPNPASRSYEOMETDGERONATEIRASVGRMVSGIGRFYI OMCTELKLSDYEGRLIONSITIERMVLSAFDERRNRYLEEHPSAGKDPKKTGGPIYRR RDGKWVRELILYDKEEIRR1WROANNGEDATAGLTHLMIWHSNLNDATYORTRALV RTGMDPRMCSLMOGSTLPRRSGAAGAAVKGVGTMVMELIRMIKRGINDRNFWRGE NGRRTRIAYERMCNIL G FOTAAORAMMDOVRESRNPGNAEIEDLIFLARSALILR GSVAHKSCLPACVYGLAVASGYDFEREGYSLVGIDPFRLLONSOVFSLIRPNENPAH KSOLVWMACHSAAFEDLRVSSFIRGTRVVPRGOLSTRGVOIASNENMEAMDSNTLE LRSRYWAIRTRSGGNTNOORASASAFTGNTEGRTSDMRTEIIRMMESARPEDVSFOG RGVFELSDEKATNPIVPSFDMSNEGSYFFGDNAEEYDNASHHHHHP SEO ID NO : 19) ATGAACAGGCTTACTTCCTCATTGCTGCTGCTGATTGTCCCTGCATATGTCCTGTC CCAGGTTACTCTGAAAGAGTCTGGCCCTGGGATATTGCAGCCCTCCCAGACCCTC AGTCTGACTTGTTCTTTCTCTGGGTTTTCACTGAGCACTTCTGGTATGGGTCTGAG CTGGATTCGTCAGCCTTCAGGAAAGGGTCTGGAGTGGCTGGCACACATTTACTGG GATGATGACAAGCGCTATAACCCATCCCTGAAGAGCCGGCTCACAATCTCCAAG GATACCTCCAGCAACCAGGTTTTCCTCAAGATCACCATTGTGGACACTGCAGATG CTGCCACATACTACTGTGCTCGAAGCTCCCATTACTACGGTTATGGCTACGGGGG ATACTTCGATGTCTGGGGCGCAGGGACCACGGTCACCGTCTCCTCAGCCAAAACG AAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCA CAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTC GTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAG TCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGG GCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGG ACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGA GTTCGAAGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTC ATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAA GACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCC AAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTC CTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGG CAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACC AAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCC TCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGAC AAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCT CTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGTC AGACCCCCACCAACACCATCAGCGTGACCCCCACCAACAACAGCACCCCCACCA ACAACAGCAACCCCAAGCCCAACCCCGCTAGTCGGTCTTACGAACAGATGGAGA CTGATGGAGAACGCCAGAATGCTACTGAGATCAGGGCATCTGTTGGAAGAATGG TTAGTGGCATTGGGAGGTTCTACATACAGATGTGCACAGAACTCAAACTCAGTGA CTATGAAGGGAGGCTGATCCAGAACAGCATAACAATAGAGAGAATGGTACTCTC TGCATTTGATGAAAGAAGGAACAGATACCTGGAAGAACACCCCAGTGCGGGAAA GGACCCGAAGAAGACTGGAGGTCCAATTTATCGGAGGAGAGACGGGAAATGGG TGAGAGAGCTAATTCTGTACGACAAAGAGGAGATCAGGAGGATTTGGCGTCAAG CGAACAATGGAGAGGACGCAACTGCTGGTCTTACCCACCTGATGATATGGCATTC CAATCTAAATGATGCCACATATCAGAGAACGAGAGCTCTCGTGCGTACTGGAAT GGACCCAAGGATGTGCTCTCTGATGCAAGGGTCAACTCTCCCGAGGAGATCTGG AGCTGCCGGTGCAGCAGTAAAGGGGGTAGGGACAATGGTGATGGAGCTGATTCG GATGATAAAACGAGGGATCAACGACCGGAATTTCTGGAGAGGCGAAAATGGAA GAAGAACAAGGATTGCATATGAGAGAATGTGCAACATCCTCAAAGGGAAATTCC AAACAGCAGCACAAAGAGCAATGATGGATCAAGTGCGAGAGAGCAGAAATCCT GGGAATGCTGAAATTGAAGATCTCATTTTTCTGGCACGGTCTGCACTCATCCTGA GAGGATCAGTGGCCCATAAGTCCTGCTTGCCTGCTTGTGTGTACGGACTTGCAGT GGCCAGTGGATATGACTTTGAGAGAGAAGGGTACTCTCTGGTTGGAATAGATCCT TTCCGCCTGCTTCAAAACAGCCAGGTCTTTAGTCTCATTAGACCAAATGAGAATC CAGCACATAAGAGTCAATTAGTGTGGATGGCATGCCACTCTGCAGCATTTGAGG ACCTTAGAGTCTCAAGTTTCATCAGAGGGACAAGAGTGGTCCCAAGAGGACAGC TATCCACCAGAGGGGTTCAAATTGCTTCAAATGAGAACATGGAGGCAATGGACT CCAACACTCTTGAACTGAGAAGCAGATATTGGGCTATAAGAACCAGAAGCGGAG GAAACACCAACCAGCAGAGGGCATCTGCTAGTGCATTTACAGGAAATACTGAGG GCAGAACGTCTGACATGAGGACTGAAATCATAAGAATGATGGAAAGTGCCAGAC CAGAAGATGTGTCATTCCAGGGGCGGGGAGTCTTCGAGCTCTCGGACGAAAAGG CAACGAACCCGATCGTGCCTTCCTTTGACATGAGTAATGAAGGATCTTATTTCTT CGGAGACAATGCAGAGGAGTACGACAATGCTAGCCACCATCACCATCACCATTA

G(SEQ ID NO :20)

[mAnti-LOX-115C4H-LV-hIgG4H-C-FluNP-5-6xHis] [NP-5 shown in double underline] EIQLQQTGPELVKPGASVKISCKASGYPFTDYIMVWVKQSHGKSLEWIGNISPYYGTT NYNLKFKGKATLTVDKSSSTAYMQLNSLTSEDSAVYYCARSPNWDGAWFAHWGQ GALVTVSAAKTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPC PPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSRLTVDKSRWOEGNVFSCSVMHEALFINHYTOKSLSLSLGKASMASO GTKRSYEOMETGGERONATEIRASVGRMVSGIGRFYIOMCTELKLSDYEGRLIONSIT IERMVLSAFDERRNRYLEEHPSAGKDPKKTGGPIYRRRDGKWVRELILYDKEEIRRI WROANNGEDATAGLTHLMIWHSNLNDATYORTRALVRTGMDPRMCSLMOGSTLP RRSGAAGAAVKGVGTMVMELIRMIKRGINDRNFWRGENGRRTRIAYERMCNILKG KFOTAAORAMMDOVRESRNPGNAEIEDLIFLARSALILRGSVAHKSCLPACVYGLAV ASGYDFEREGYSLVGIDPFRLLONSOVFSLIRPNENPAHKSQLVWMACHSAAFEDLR VSSFIRGTRVVPRGOLSTRGVOIASNENMEAMDSNTLELRSRYWAIRTRSGGNTNOO RASAGOISVOPTFSVORNLPFERATIMAAFTGNTEGRTSDMRTEIIRMMESARPEDVS FOGRGVFELSDEKATNPIVPSFDMNNEGSYFFGDNAEEYDNHHHHHHCSEO ID NO

:21)

ATGGGAGGGATCTGGATCTTTCTCTTCCTCCTGTCAGGAACTGCAGGTGCCCACT CTGAGATCCAGCTGCAGCAGACTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAG TGAAGATATCCTGCAAGGCTTCTGGTTATCCATTCACTGACTACATCATGGTCTG GGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGAAATATTAGTCCTTA CTATGGTACT ACT AACTAC A ATCTGAAGTTC AAGGGC A AGGCC AC ATTGACTGTA GACAAATCTTCCAGCACAGCCTACATGCAGCTCAACAGTCTGACATCTGAGGACT CTGCAGTCTATTACTGTGCAAGATCCCCTAACTGGGACGGGGCCTGGTTTGCTCA CTGGGGCCAAGGGGCTCTGGTCACTGTCTCTGCAGCCAAAACAAAGGGCCCATC CGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTG GGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAG GCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACT CTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACC TACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTT GAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGGGG GACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCG GACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGT CCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCC GCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCT GCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGG CCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA GCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGT CAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGG GAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGC AGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTA CACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGCATGGCGTCTCAAGGC ACCAAACGATCTTATGAACAGATGGAAACTGGTGGGGAACGCCAGAATGCTACT GAGATCAGGGCATCTGTTGGAAGAATGGTTAGTGGCATTGGGAGGTTCTACATA CAGATGTGCACAGAACTCAAACTCAGTGACTATGAAGGGAGGCTGATCCAGAAC AGCATAACAATAGAGAGAATGGTACTCTCTGCATTTGATGAAAGAAGGAACAGA TACCTGGAAGAACACCCCAGTGCGGGAAAGGACCCGAAGAAGACTGGAGGTCC AATTTATCGGAGGAGAGACGGGAAATGGGTGAGAGAGCTAATTCTGTACGACAA AGAGGAGATCAGGAGGATTTGGCGTCAAGCGAACAATGGAGAGGACGCAACTG CTGGTCTTACCCACCTGATGATATGGCATTCCAATCTAAATGATGCCACATATCA GAGAACGAGAGCTCTCGTGCGTACTGGAATGGACCCAAGGATGTGCTCTCTGAT GCAAGGGTCAACTCTCCCGAGGAGATCTGGAGCTGCCGGTGCAGCAGTAAAGGG GGTAGGGACAATGGTGATGGAGCTGATTCGGATGATAAAACGAGGGATCAACGA CCGGAATTTCTGGAGAGGCGAAAATGGAAGAAGAACAAGGATTGCATATGAGA GAATGTGCAACATCCTCAAAGGGAAATTCCAAACAGCAGCACAAAGAGCAATGA TGGATCAAGTGCGAGAGAGCAGAAATCCTGGGAATGCTGAAATTGAAGATCTCA TTTTTCTGGCACGGTCTGCACTCATCCTGAGAGGATCAGTGGCCCATAAGTCCTG CTTGCCTGCTTGTGTGTACGGACTTGCAGTGGCCAGTGGATATGACTTTGAGAGA GAAGGGTACTCTCTGGTTGGAATAGATCCTTTCCGCCTGCTTCAAAACAGCCAGG TCTTTAGTCTCATTAGACCAAATGAGAATCCAGCACATAAGAGTCAATTAGTGTG GATGGCATGCCACTCTGCAGCATTTGAGGACCTTAGAGTCTCAAGTTTCATCAGA GGGACAAGAGTGGTCCCAAGAGGACAGCTATCCACCAGAGGGGTTCAAATTGCT TCAAATGAGAACATGGAGGCAATGGACTCCAACACTCTTGAACTGAGAAGCAGA TATTGGGCTATAAGAACCAGAAGCGGAGGAAACACCAACCAGCAGAGGGCATCT GCAGGACAGATCAGCGTTCAGCCCACTTTCTCGGTCCAGAGAAACCTTCCCTTTG AAAGAGCGACCATTATGGCAGCATTTACAGGAAATACTGAGGGCAGAACGTCTG ACATGAGGACTGAAATCATAAGAATGATGGAAAGTGCCAGACCAGAAGATGTGT CATTCCAGGGGCGGGGAGTCTTCGAGCTCTCGGACGAAAAGGCAACGAACCCGA TCGTGCCTTCCTTTGACATGAATAATGAAGGATCTTATTTCTTCGGAGACAATGC AGAGGAGTATGACAATCACCATCACCATCACCATTAA(SEQ ID NO :22)

[mAnti-Langerinl5B10H-LV-hIgG4H-C-FluNP-5-6xHis] [NP-5 shown in double underline]

QVQLRQSGPELVKPGASVKMSCKASGYTFTDYVISWVKQRTGQGLEWIGDIYPGSG YSFYNENFKGKATLTADKSSTTAYMQLSSLTSEDSAVYFCATYYNYPFAYWGQGTL VTVSAAKTTGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGT TYTCNVDHKPSNTKVDKRVESKYGPPCPPCPA PEFEGGP S VFLFPPKP DTLMI SRTPEVTC V V VD V S QEDPEVQFN W Y VDGVEVFIN AK TKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSD1AVEWESNGQPENNYKTTPPVLDSDG SFFLYSRLTVDKSRWOEGNVFSCSVMHEALHNHYTOKSLSLSLGKASMASOGTKRS YEOMETGGERONATEIRASVGRMVSGIGRFYIOMCTELKLSDYEGRLIONSITIERMV LSAFDERRNRYLEEHPSAGKDPKKTGGPIYRRRDGKWVRELILYDKEEIRRIWROAN NGEDATAGLTHLMIWHSNLNDATYORTRALVRTGMDPRMCSLMOGSTLPRRSGAA GAAVKGVGTMVMELIRMIKRGINDRNFWRGENGRRTRIAYERMCNILKGKFOTAA ORAMMDOVRESRNPGNAEIEDL1FLARSALILRGSVAHKSCLPACVYGLAVASGYDF EREGYSLVGIDPFRLLONSOVFSLIRPNENPAH SOLVWMACHSAAFEDLRVSSFI G TRVVPRGOLSTRGVOIASNENMEAMDSNTLELRSRYWAIRTRSGGNTNOORASAGO ISVOPTFSVORNLPFERATIMAAFTGNTEGRTSDMRTEIIRMMESARPEDVSFOGRGV FELSDEKATNPIVPSFDMN EGSYFFGDNAEEYDNHHHHHHfSEO ID NO :23)

ATGGAATGGAGGATCTTTCTCTTCATCCTGTCAGGAACTGCAGGTGTCCACTCCC AGGTTCAGCTGCGGCAGTCTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAGTGA AGATGTCCTGCAAGGCTTCTGGATACACATTTACTGACTATGTTATAAGTTGGGT GAAGCAGAGAACTGGACAGGGCCTTGAGTGGATTGGAGATATTTATCCTGGAAG TGGTTATTCTTTCTACAATGAGAACTTCAAGGGCAAGGCCACACTGACTGCAGAC AAATCCTCCACCACAGCCTACATGCAGCTCAGCAGCCTGACATCTGAGGACTCTG CGGTCTATTTCTGTGCAACCTACTATAACTACCCTTTTGCTTACTGGGGCCAAGGG ACTCTGGTCACTGTCTCTGCAGCCAAAACAACGGGCCCATCCGTCTTCCCCCTGG CGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCA AGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCA GCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAG CAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAA CGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATA TGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGG TCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACT GGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAG CAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCT CCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGT ACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT GCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATG GGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCT CCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAA GAGCCTCTCCCTGTCTCTGGGTAAAGCTAGCATGGCGTCTCAAGGCACCAAACGA TCTTATGAACAGATGGAAACTGGTGGGGAACGCCAGAATGCTACTGAGATCAGG GCATCTGTTGGAAGAATGGTTAGTGGCATTGGGAGGTTCTACATACAGATGTGCA CAGAACTCAAACTCAGTGACTATGAAGGGAGGCTGATCCAGAACAGCATAACAA TAGAGAGAATGGTACTCTCTGC ATTTGATGAA AGAAGGAACAGATACCTGGAAG AACACCCCAGTGCGGGAAAGGACCCGAAGAAGACTGGAGGTCCAATTTATCGGA GGAGAGACGGGAAATGGGTGAGAGAGCTAATTCTGTACGACAAAGAGGAGATC AGGAGGATTTGGCGTCAAGCGAACAATGGAGAGGACGCAACTGCTGGTCTTACC CACCTGATGATATGGCATTCCAATCTAAATGATGCCACATATCAGAGAACGAGA GCTCTCGTGCGTACTGGAATGGACCCAAGGATGTGCTCTCTGATGCAAGGGTCAA CTCTCCCGAGGAGATCTGGAGCTGCCGGTGCAGCAGTAAAGGGGGTAGGGACAA TGGTGATGGAGCTGATTCGGATGATAAAACGAGGGATCAACGACCGGAATTTCT GGAGAGGCGAAAATGGAAGAAGAACAAGGATTGCATATGAGAGAATGTGCAAC ATCCTCAAAGGGAAATTCCAAACAGCAGCACAAAGAGCAATGATGGATCAAGTG CGAGAGAGCAGAAATCCTGGGAATGCTGAAATTGAAGATCTCATTTTTCTGGCAC GGTCTGCACTCATCCTGAGAGGATCAGTGGCCCATAAGTCCTGCTTGCCTGCTTG TGTGTACGGACTTGCAGTGGCCAGTGGATATGACTTTGAGAGAGAAGGGTACTCT CTGGTTGGAATAGATCCTTTCCGCCTGCTTCAAAACAGCCAGGTCTTTAGTCTCAT TAGACCAAATGAGAATCCAGCACATAAGAGTCAATTAGTGTGGATGGCATGCCA CTCTGCAGCATTTGAGGACCTTAGAGTCTCAAGTTTCATCAGAGGGACAAGAGTG GTCCCAAGAGGACAGCTATCCACCAGAGGGGTTCAAATTGCTTCAAATGAGAAC ATGGAGGCAATGGACTCCAACACTCTTGAACTGAGAAGCAGATATTGGGCTATA AGAACCAGAAGCGGAGGAAACACCAACCAGCAGAGGGCATCTGCAGGACAGAT CAGCGTTCAGCCCACTTTCTCGGTCCAGAGAAACCTTCCCTTTGAAAGAGCGACC ATTATGGCAGCATTTACAGGAAATACTGAGGGCAGAACGTCTGACATGAGGACT GAAATCATAAGAATGATGGAAAGTGCCAGACCAGAAGATGTGTCATTCCAGGGG CGGGGAGTCTTCGAGCTCTCGGACGAAAAGGCAACGAACCCGATCGTGCCTTCC TTTGACATGAATAATGAAGGATCTTATTTCTTCGGAGACAATGCAGAGGAGTATG ACAATCACCATCACCATCACCATTAA(SEQ ID NO :24)

[manti-Dectin 1 15E2.5_H-V-hIgG4H-C-FluNP-5-6xHis] [NP-5 shown in double underline]

QVQLQQSGAELARPGASVKMSCKASGYTFTTYTMHWVKQRPGQGLEWIGYINPSSG YTNYNQKFKDKATLTADKSSSTASMQLSSLTSEDSAVYYCARERAVLVPYAMDYW GQGTSVTVSSAKTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDH PSNTKVDKRVESKYGPP CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEY CKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMT NQVSLTCLVKGFYPSDIAVEWESNGQPEN YKTTPPV LDSDGSFFLYSRLTVDKSRWOEGNVFSCSVMHEALHNHYTOKSLSLSLG ASMASO GTKRSYEOMETGGERONATEIRASVGRMVSGIGRFYIOMCTELKLSDYEGRLIONSIT IERMVLSAFDERRNRYLEEHPSAGKDPKKTGGPIYRRRDGKWVRELILYDKEEIRRI WROANNGEDATAGLTHLMIWHSNLNDATYORTRALVRTGMDPRMCSLMOGSTLP RRSGAAGAAVKGVGTMVMELIRMIKRGINDRNFWRGENGRRTRIAYERMCNILKG KFOTAAORAMMDOVRESRNPGNAEIEDLIFLARSALILRGSVAHKSCLPACVYGLAV ASGYDFEREGYSLVGIDPFRLLONSOVFSLIRPNENPAHKSOLVWMACHSAAFEDLR VSSFIRGTRVVPRGOLSTRGVOIASNENMEAMDSNTLELRSRYWAIRTRSGGNTNOO RASAGOISVOPTFSVORNLPFERATIMAAFTGNTEGRTSDMRTEIIRMMESARPEDVS FOGRGVFELSDEKATNPIVPSFDMNNEGSYFFGDNAEEYDNHHHHHHiSEO ID NO :25)

ATGGAAAGGCACTGGATCTTTCTACTCCTGTTGTCAGTAACTGCAGGTGTCCACT CCCAGGTCCAGCTGCAGCAGTCTGGGGCTGAACTGGCAAGACCTGGGGCCTCAG TGAAGATGTCCTGCAAGGCTTCTGGCTACACCTTTACTACCTACACTATGCACTG GGTAAAACAGAGGCCTGGACAGGGTCTGGAATGGATTGGATACATTAATCCTAG CAGTGGTTATACTAATTACAATCAGAAGTTCAAGGACAAGGCCACATTGACTGC AGACAAATCCTCCAGCACAGCCTCCATGCAACTGAGCAGCCTGACATCTGAGGA CTCTGCAGTCTATTACTGTGCAAGAGAGAGGGCGGTATTAGTCCCCTATGCTATG GACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCAGCCAAAACAAAGGGC CCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCG CCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAA CTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGA AGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGA GAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGA AGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATC TCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCC GAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACC GTCCTGC ACC AGGACTGGCTGAACGGC AAGGAGTACAAGTGC AAGGTCTCC AAC AAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAAC CAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGG AGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAG GTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGCATGGCGTCTC AAGGCACCAAACGATCTTATGAACAGATGGAAACTGGTGGGGAACGCCAGAATG CTACTGAGATCAGGGCATCTGTTGGAAGAATGGTTAGTGGCATTGGGAGGTTCTA C ATAC AGATGTGCACAGAACTC AAACTCAGTGACTATGAAGGGAGGCTGATCC A GAACAGCATAACAATAGAGAGAATGGTACTCTCTGCATTTGATGAAAGAAGGAA CAGATACCTGGAAGAACACCCCAGTGCGGGAAAGGACCCGAAGAAGACTGGAG GTCCAATTTATCGGAGGAGAGACGGGAAATGGGTGAGAGAGCTAATTCTGTACG ACAAAGAGGAGATCAGGAGGATTTGGCGTCAAGCGAACAATGGAGAGGACGCA ACTGCTGGTCTTACCCACCTGATGATATGGCATTCCAATCTAAATGATGCCACAT ATCAGAGAACGAGAGCTCTCGTGCGTACTGGAATGGACCCAAGGATGTGCTCTC TGATGCAAGGGTCAACTCTCCCGAGGAGATCTGGAGCTGCCGGTGCAGCAGTAA AGGGGGTAGGGACAATGGTGATGGAGCTGATTCGGATGATAAAACGAGGGATCA ACGACCGGAATTTCTGGAGAGGCGAAAATGGAAGAAGAACAAGGATTGCATATG AGAGAATGTGCAACATCCTCAAAGGGAAATTCCAAACAGCAGCACAAAGAGCA ATGATGGATCAAGTGCGAGAGAGCAGAAATCCTGGGAATGCTGAAATTGAAGAT CTCATTTTTCTGGCACGGTCTGCACTCATCCTGAGAGGATCAGTGGCCCATAAGT CCTGCTTGCCTGCTTGTGTGTACGGACTTGCAGTGGCCAGTGGATATGACTTTGA GAGAGAAGGGTACTCTCTGGTTGGAATAGATCCTTTCCGCCTGCTTCAAAACAGC CAGGTCTTTAGTCTCATTAGACCAAATGAGAATCCAGCACATAAGAGTCAATTAG TGTGGATGGCATGCCACTCTGCAGCATTTGAGGACCTTAGAGTCTCAAGTTTCAT CAGAGGGACAAGAGTGGTCCCAAGAGGACAGCTATCCACCAGAGGGGTTCAAAT TGCTTCAAATGAGAACATGGAGGCAATGGACTCCAACACTCTTGAACTGAGAAG CAGATATTGGGCTATAAGAACCAGAAGCGGAGGAAACACCAACCAGCAGAGGG C ATCTGCAGGACAGATCAGCGTTC AGCCC ACTTTCTCGGTCC AGAGAAACCTTCC CTTTGAAAGAGCGACCATTATGGCAGCATTTACAGGAAATACTGAGGGCAGAAC GTCTGACATGAGGACTGAAATCATAAGAATGATGGAAAGTGCCAGACCAGAAGA TGTGTCATTCCAGGGGCGGGGAGTCTTCGAGCTCTCGGACGAAAAGGCAACGAA CCCGATCGTGCCTTCCTTTGACATGAATAATGAAGGATCTTATTTCTTCGGAGAC AATGCAGAGGAGTATGACAATCACCATCACCATCACCATTAA(SEQ ID NO :26)

[manti-CD40_12E12.3F3_H-V-hIgG4H-C-Flex-vl-FluNP-5-6xHis] [NP-5 shown in double underline; Flex-vl shown in single underline]

EVKLVESGGGLVQPGGSLKLSCATSGFTFSDYYMYWVRQTPEKRLEWVAYINSGGG STYYPDTVKGRFTISRDNAKNTLYLQMSRLKSEDTAMYYCARRGLPFHAMDYWGQ GTSVTVSSAKTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPP CPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQ PREPQVYTLPPSQEEMT NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKASQTPTNTI SVTPTNNSTPTNNSNPKPNPASMASOGTKRSYEOMETGGERONATEIRASVGRMVS GIGRFYIOMCTELKLSDYEGRLIONSITIERMVLSAFDERRNRYLEEHPSAGKDPKKT GGPIYRRRDGKWVRELILYDKEEIRRIWROANNGEDATAGLTHLMIWHSNLNDATY ORTRALVRTGMDPRMCSLMOGSTLPRRSGAAGAAV GVGTMVMELIRMIKRGIND RNFWRGENGRRTRIAYERMCNILKGKFOTAAORAMMDOVRESRNPGNAEIEDLIFL ARSALILRGSVAHKSCLPACVYGLAVASGYDFEREGYSLVGIDPFRLLONSQVFSLIR PNENPAHKSOLVWMACHSAAFEDLRVSSFIRGTRVVPRGQLSTRGVOIASNENMEA MDSNTLELRSRYWAIRTRSGGNTNOQRASAGOISVOPTFSVORNLPFERATIMAAFT GNTEGRTSDMRTEIIRMMESARPEDVSFOGRGVFELSDEKATNPIVPSFDMNNEGSYF FGDNAEEYDNHHHHHHiSEO ID NO :27)

ATGAACTTGGGGCTCAGCTTGATTTTCCTTGTCCTTGTTTTAAAAGGTGTCCAGTG TGAAGTGAAGCTGGTGGAGTCTGGGGGAGGCTTAGTGCAGCCCGGAGGGTCCCT GAAACTCTCCTGTGC AACCTCTGG ATTC ACTTTC AGTGACTATTAC ATGTATTGGG TTCGCCAGACTCCAGAGAAGAGGCTGGAGTGGGTCGCATACATTAATTCTGGTG GTGGTAGCACCTATTATCCAGACACTGTAAAGGGCCGATTCACCATCTCCAGAGA CAATGCCAAGAACACCCTGTACCTGCAAATGAGCCGGCTGAAGTCTGAGGACAC AGCCATGTATTACTGTGCAAGACGGGGGTTACCGTTCCATGCTATGGACTATTGG GGTCAAGGAACCTCAGTCACCGTCTCCTCAGCCAAAACGAAGGGCCCATCCGTCT TCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCC CTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACT CCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACA CCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGT CCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGGGGGACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAG TTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGG GAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACC AGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCC CGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCAC AGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCC TGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCG ACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGG AGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACAC ACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGTCAGACCCCCACCAACACC ATCAGCGTGACCCCCACCAACAACAGCACCCCCACCAACAACAGCAACCCCAAG CCC AACCCCGCTAGC ATGGCGTCTC AAGGCACCAAACGATCTTATGAACAGATG GAAACTGGTGGGGAACGCCAGAATGCTACTGAGATCAGGGCATCTGTTGGAAGA ATGGTTAGTGGCATTGGGAGGTTCTACATACAGATGTGCACAGAACTCAAACTCA GTGACTATGAAGGGAGGCTGATCCAGAACAGCATAACAATAGAGAGAATGGTAC TCTCTGCATTTGATGAAAGAAGGAACAGATACCTGGAAGAACACCCCAGTGCGG GAAAGGACCCGAAGAAGACTGGAGGTCCAATTTATCGGAGGAGAGACGGGAAA TGGGTGAGAGAGCTAATTCTGTACGACAAAGAGGAGATCAGGAGGATTTGGCGT CAAGCGAACAATGGAGAGGACGCAACTGCTGGTCTTACCCACCTGATGATATGG CATTCCAATCTAAATGATGCCACATATCAGAGAACGAGAGCTCTCGTGCGTACTG GAATGGACCCAAGGATGTGCTCTCTGATGCAAGGGTCAACTCTCCCGAGGAGAT CTGGAGCTGCCGGTGCAGCAGTAAAGGGGGTAGGGACAATGGTGATGGAGCTGA TTCGGATGATAAAACGAGGGATCAACGACCGGAATTTCTGGAGAGGCGAAAATG GAAGAAGAACAAGGATTGCATATGAGAGAATGTGCAACATCCTCAAAGGGAAAT TCCAAACAGCAGCACAAAGAGCAATGATGGATCAAGTGCGAGAGAGCAGAAAT CCTGGGAATGCTGAAATTGAAGATCTCATTTTTCTGGCACGGTCTGCACTCATCC TGAGAGGATCAGTGGCCCATAAGTCCTGCTTGCCTGCTTGTGTGTACGGACTTGC AGTGGCCAGTGGATATGACTTTGAGAGAGAAGGGTACTCTCTGGTTGGAATAGA TCCTTTCCGCCTGCTTCAAAACAGCCAGGTCTTTAGTCTCATTAGACCAAATGAG AATCCAGCACATAAGAGTCAATTAGTGTGGATGGCATGCCACTCTGCAGCATTTG AGGACCTTAGAGTCTCAAGTTTCATCAGAGGGACAAGAGTGGTCCCAAGAGGAC AGCTATCCACCAGAGGGGTTCAAATTGCTTCAAATGAGAACATGGAGGCAATGG ACTCCAACACTCTTGAACTGAGAAGCAGATATTGGGCTATAAGAACCAGAAGCG GAGGAAACACCAACCAGCAGAGGGCATCTGCAGGACAGATCAGCGTTCAGCCCA CTTTCTCGGTCCAGAGAAACCTTCCCTTTGAAAGAGCGACCATTATGGCAGCATT TACAGGAAATACTGAGGGCAGAACGTCTGACATGAGGACTGAAATCATAAGAAT GATGGAAAGTGCCAGACCAGAAGATGTGTCATTCCAGGGGCGGGGAGTCTTCGA GCTCTCGGACGAAAAGGCAACGAACCCGATCGTGCCTTCCTTTGACATGAATAAT GAAGGATCTTATTTCTTCGGAGACAATGCAGAGGAGTATGACAATCACCATCACC ATCACCATTAA(SEQ ID NO :28) [mAnti-DCIR_9E8_H-LV-hIgG4H-C-Flex-vl-FIuNP-l-6xHis] [NP-1 shown in double underline; Flex-vl shown in single underline]

QVTLKESGPGILQPSQTLSLTCSFSGFSLSTSGMGLSWIRQPSGKGLEWLAHIYWDDD KRYNPSLKSRLTIS DTSSNQVFLKITIVDTADAATYYCARSSHYYGYGYGGYFDVW GAGTTVTVSSAKTKGPSVFPLAPCSRSTSESTAALGCLV DYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNA TKPREEQFNSTYRVVSVLTVLHQDWLNG EY CKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLV GFYPSDIAVEWESNGQPEN YKTTPPV LDSDGSFFLYSRLTVD SRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKASQTPTN TISVTPTNNSTPTNNSNPKPNPASMASOGTKRSYEOMETDGERONATEIRASVGKMI GGIGRFYIOMCTELKLSDYEGRLIONSLTIERMVLSAFDERRNKYLEEHPSAGKDPK TGGPIYRRVNGKWMRELILYDKEEIRRIWROANNGDDATAGLTHMMIWHSNLNDA TYORTRALVRTGMDPRMCSLMOGSTLPRRSGAAGAAVKGVGTMVMELVRMIKRGI NDRNFWRGENGRKTRIAYERMCNILKGKFOTAAOKAMMDOVRESRNPGNAEFEDL TFLARSALILRGSVAHKSCLPACVYGPAVASGYDFEREGYSLVGIDPFRLLONSOVYS LIRPNENPAHKSOLVWMACHSAAFEDLRVLSFIKGTKVLPRGKLSTRGVOIASNENM ETMESSTLELRSRYWAIRTRSGGNTNOORASAGOISIOPTFSVORNLPFDRTTIMAAF NGNTEGRTSDMRTEIIRMMESARPEDVSFOGRGVFELSDEKAASPIVPSFDMSNEGSY FFGDNAEEYDNASHHHHHHfSEO ID NO :29)

ATGAACAGGCTTACTTCCTCATTGCTGCTGCTGATTGTCCCTGCATATGTCCTGTC CCAGGTTACTCTGAAAGAGTCTGGCCCTGGGATATTGCAGCCCTCCCAGACCCTC AGTCTGACTTGTTCTTTCTCTGGGTTTTCACTGAGCACTTCTGGTATGGGTCTGAG CTGGATTCGTCAGCCTTCAGGAAAGGGTCTGGAGTGGCTGGCACACATTTACTGG GATGATGACAAGCGCTATAACCCATCCCTGAAGAGCCGGCTCACAATCTCCAAG GATACCTCCAGCAACCAGGTTTTCCTCAAGATCACCATTGTGGACACTGCAGATG CTGCCACATACTACTGTGCTCGAAGCTCCCATTACTACGGTTATGGCTACGGGGG ATACTTCGATGTCTGGGGCGCAGGGACCACGGTCACCGTCTCCTCAGCCAAAACG AAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCA CAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTC GTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAG TCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGG GCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGG ACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGA GTTCGAAGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTC ATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAA GACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCC AAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTC CTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGG CAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACC AAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCC TCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGAC AAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCT CTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGTC AGACCCCCACCAACACCATCAGCGTGACCCCCACCAACAACAGCACCCCCACCA ACAACAGCAACCCCAAGCCCAACCCCGCTAGTATGGCGTCCCAAGGCACCAAAC GGTCTTACGAACAGATGGAGACTGATGGAGAACGCCAGAATGCCACTGAAATCA GAGCATCCGTCGGAAAAATGATTGGTGGAATTGGACGATTCTACATCCAAATGT GCACCGAACTCAAACTCAGTGATTATGAGGGACGGTTGATCCAAAACAGCTTAA CAATAGAGAGAATGGTGCTCTCTGCTTTTGACGAAAGGAGAAATAAATACCTGG AAGAACATCCCAGTGCGGGGAAAGATCCTAAGAAAACTGGAGGACCTATATACA GGAGAGTAAACGGAAAGTGGATGAGAGAACTCATCCTTTATGACAAAGAAGAA ATAAGGCGAATCTGGCGCCAAGCTAATAATGGTGACGATGCAACGGCTGGTCTG ACTCACATGATGATCTGGCATTCCAATTTGAATGATGCAACTTATCAGAGGACAA GAGCTCTTGTTCGCACCGGAATGGATCCCAGGATGTGCTCTCTGATGCAAGGTTC AACTCTCCCTAGGAGGTCTGGAGCCGCAGGTGCTGCAGTCAAAGGAGTTGGAAC AATGGTGATGGAATTGGTCAGGATGATCAAACGTGGGATCAATGATCGGAACTT CTGGAGGGGTGAGAATGGACGAAAAACAAGAATTGCTTATGAAAGAATGTGCAA CATTCTCAAAGGGAAATTTCAAACTGCTGCACAAAAAGCAATGATGGATCAAGT GAGAGAGAGCCGGAACCCAGGGAATGCTGAGTTCGAAGATCTCACTTTTCTAGC ACGGTCTGCACTCATATTGAGAGGGTCGGTTGCTCACAAGTCCTGCCTGCCTGCC TGTGTGTATGGACCTGCCGTAGCCAGTGGGTACGACTTTGAAAGAGAGGGATAC TCTCTAGTCGGAATAGACCCTTTCAGACTGCTTCAAAACAGCCAAGTGTACAGCC TAATCAGACCAAATGAGAATCCAGCACACAAGAGTCAACTGGTGTGGATGGCAT GCCATTCTGCCGCATTTGAAGATCTAAGAGTATTAAGCTTCATCAAAGGGACGAA GGTGCTCCCAAGAGGGAAGCTTTCCACTAGAGGAGTTCAAATTGCTTCCAATGAA AATATGGAGACTATGGAATCAAGTACACTTGAACTGAGAAGCAGGTACTGGGCC ATAAGGACCAGAAGTGGAGGAAACACCAATCAACAGAGGGCATCTGCGGGCCA AATCAGCATACAACCTACGTTCTCAGTACAGAGAAATCTCCCTTTTGACAGAACA ACCATTATGGCAGCATTCAATGGGAATACAGAGGGAAGAACATCTGACATGAGG ACCGAAATCATAAGGATGATGGAAAGTGCAAGACCAGAAGATGTGTCTTTCCAG GGGCGGGGAGTCTTCGAGCTCTCGGACGAAAAGGCAGCGAGCCCGATCGTGCCT TCCTTTGACATGAGTAATGAAGGATCTTATTTCTTCGGAGACAATGCAGAGGAGT ACGACAATGCTAGCCACCATCACCATCACCATTAG(SEQ ID NO :30)

[mAnti-DCIR_9E8_H-LV-hIgG4H-C-Flex-vl-M2e-B-FluNP-l-6xHis ] [NP-1 shown in double underline; Flex-vl and O shown in single underline; M2e shown in dashed line]

QVTLKESGPGILQPSQTLSLTCSFSGFSLSTSGMGLSWIRQPSGKGLEWLAHIYWDD D KRYNPSLKSRLTISKDTSSNQVFLKITIVDTADAATYYCARSSHYYGYGYGGYFDVW GAGTTVTVSSAKTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPP CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKASQTPTN TISVTPTNNSTPTN SNPKPNPASLLTEVETPIRNEWGCRCNGSSDPASTVTPTATATP SAIVTTITPTATTKPASMASOGTKRSYEOMETDGERONATEIRASVGKM

OMCTELKLSDYEGRLIONSLTIERMVLSAFDERRNKYLEEHPSAGKDPKKTGGPIYR RVNGKWMRELILYDKEEIRRIWROANNGDDATAGLTHMMIWHSNLNDATYORTRA LVRTGMDPRMCSLMOGSTLPRRSGAAGAAVKGVGTMVMELVRMIKRGINDRNFW RGENGRKTRIAYERMCNILKGKFOTAAOKAMMDOVRESRNPGNAEFEDLTFLARSA LILRGSVAHKSCLPACVYGPAVASGYDFEREGYSLVGIDPFRLLONSOVYSLIRPNEN PAHKSOLVWMACHSAAFEDLRVLSFIKGTKVLPRG LSTRGVOIASNENMETMESST LELRSRYWAIRTRSGGNTNOORASAGOISIOPTFSVORNLPFDRTTIMAAFNGNTEGR TSDMRTEIIRMMESARPEDVSFOGRGVFELSDEKAASPIVPSFDMSNEGSYFFGDNAE EYDNASHHHHHHCSEO ID NO :31)

ATGAACAGGCTTACTTCCTCATTGCTGCTGCTGATTGTCCCTGCATATGTCCTGTC CCAGGTTACTCTGAAAGAGTCTGGCCCTGGGATATTGCAGCCCTCCCAGACCCTC AGTCTGACTTGTTCTTTCTCTGGGTTTTCACTGAGCACTTCTGGTATGGGTCTGAG CTGGATTCGTCAGCCTTCAGGAAAGGGTCTGGAGTGGCTGGCACACATTTACTGG GATGATGACAAGCGCTATAACCCATCCCTGAAGAGCCGGCTCACAATCTCCAAG GATACCTCCAGCAACCAGGTTTTCCTCAAGATCACCATTGTGGACACTGCAGATG CTGCCACATACTACTGTGCTCGAAGCTCCCATTACTACGGTTATGGCTACGGGGG ATACTTCGATGTCTGGGGCGCAGGGACCACGGTCACCGTCTCCTCAGCCAAAACG AAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCA CAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTC GTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAG TCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGG GCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGG ACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGA GTTCGAAGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTC ATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAA GACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCC AAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTC CTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGG CAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACC AAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCC TCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGAC AAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCT CTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGTC AGACCCCCACCAACACCATCAGCGTGACCCCCACCAACAACAGCACCCCCACCA ACAACAGCAACCCCAAGCCCAACCCCGCTAGTCTGCTGACAGAGGTGGAGACCC CTATCCGGAATGAATGGGGATGCCGGTGTAACGGCAGCAGCGACCCCGCTAGTA CCGTGACCCCCACCGCCACCGCCACCCCCAGCGCCATCGTGACCACCATCACCCC CACCGCCACCACCAAGCCCGCTAGTATGGCGTCCCAAGGCACCAAACGGTCTTA CGAACAGATGGAGACTGATGGAGAACGCCAGAATGCCACTGAAATCAGAGCATC CGTCGGAAAAATGATTGGTGGAATTGGACGATTCTACATCCAAATGTGCACCGA ACTCAAACTCAGTGATTATGAGGGACGGTTGATCCAAAACAGCTTAACAATAGA GAGAATGGTGCTCTCTGCTTTTGACGAAAGGAGAAATAAATACCTGGAAGAACA TCCCAGTGCGGGGAAAGATCCTAAGAAAACTGGAGGACCTATATACAGGAGAGT AAACGGAAAGTGGATGAGAGAACTCATCCTTTATGACAAAGAAGAAATAAGGCG AATCTGGCGCCAAGCTAATAATGGTGACGATGCAACGGCTGGTCTGACTCACAT GATGATCTGGCATTCCAATTTGAATGATGCAACTTATCAGAGGACAAGAGCTCTT GTTCGCACCGGAATGGATCCCAGGATGTGCTCTCTGATGCAAGGTTCAACTCTCC CTAGGAGGTCTGGAGCCGCAGGTGCTGCAGTCAAAGGAGTTGGAACAATGGTGA TGGAATTGGTCAGGATGATCAAACGTGGGATCAATGATCGGAACTTCTGGAGGG GTGAGAATGGACGAAAAACAAGAATTGCTTATGAAAGAATGTGCAACATTCTCA AAGGGAAATTTCAAACTGCTGCACAAAAAGCAATGATGGATCAAGTGAGAGAGA GCCGGAACCCAGGGAATGCTGAGTTCGAAGATCTCACTTTTCTAGCACGGTCTGC ACTCATATTGAGAGGGTCGGTTGCTCACAAGTCCTGCCTGCCTGCCTGTGTGTAT GGACCTGCCGTAGCCAGTGGGTACGACTTTGAAAGAGAGGGATACTCTCTAGTC GGAATAGACCCTTTCAGACTGCTTCAAAACAGCCAAGTGTACAGCCTAATCAGA CCAAATGAGAATCCAGCACACAAGAGTCAACTGGTGTGGATGGCATGCCATTCT GCCGCATTTGAAGATCTAAGAGTATTAAGCTTCATCAAAGGGACGAAGGTGCTC CCAAGAGGGAAGCTTTCCACTAGAGGAGTTCAAATTGCTTCCAATGAAAATATG GAGACTATGGAATCAAGTACACTTGAACTGAGAAGCAGGTACTGGGCCATAAGG ACCAGAAGTGGAGGAAACACCAATCAACAGAGGGCATCTGCGGGCCAAATCAG CATACAACCTACGTTCTCAGTACAGAGAAATCTCCCTTTTGACAGAACAACCATT ATGGCAGCATTCAATGGGAATACAGAGGGAAGAACATCTGACATGAGGACCGAA ATCATAAGGATGATGGAAAGTGCAAGACCAGAAGATGTGTCTTTCCAGGGGCGG GGAGTCTTCGAGCTCTCGGACGAAAAGGCAGCGAGCCCGATCGTGCCTTCCTTTG ACATGAGTAATGAAGGATCTTATTTCTTCGGAGACAATGCAGAGGAGTACGACA ATGCTAGCCACCATCACCATCACCATTAG(SEQ ID NO :32)

[mAnti-Langerin2G3H-LV-hIgG4H-C-Dockerin-v2-FluNP-l-6xHis ] [NP-1 shown in double underline; Dockerin-v2 shown in single underline]

EVQLVESGGGLVQPKGSLKLSCAASGLTFNIYAMNWVRQAPGKGLEWVARIRNKSN NYATYYADSVKDRFTISRDDSQSLLYLQMNNLKTEDTAMYYCVGRDWFDYWGQG TLVTVSAAKT GPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPP CPAPEFEGGPSVFLFPPKP DTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQ PREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCS VMHEALHNHYTQKSLSLSLG AS SEDTOPP APTLIGDVNADGKIDSTDLTLLKRYLLRSATLTEEKILNADTDGNGTVNSTDLNYLK KYILRVISVFPAEGNKPPTPTPTKTPVATPSPTQPLFTPSFKDVTASMASOGTKRSYEO METDGERONATEIRASVGKMIGGIGRFYIOMCTELKLSDYEGRLIONSLTIERMVLSA FDERRNKYLEEHPSAGKDPKKTGGPIYRRVNGKWMRELILYDKEEIRRIWROANNG DDATAGLTHMMIWHSNLNDATYORTRALVRTGMDPRMCSLMOGSTLPRRSGAAG AAVKGVGTMVMELVRMIKRGINDRNFWRGENGRKTRIAYERMCNILKGKFOTAAO KAMMDOVRESRNPGNAEFEDLTFLARSALILRGSVAHKSCLPACVYGPAVASGYDF EREGYSLVGIDPFRLLONSOVYSLIRPNENPAHKSOLVWMACHSAAFEDLRVLSFIKG TKVLPRGKLSTRGVOIASNENMETMESSTLELRSRYWAIRTRSGGNTNOORASAGOI SIOPTFSVORNLPFDRTTIMAAFNGNTEGRTSDMRTEIIRMMESARPEDVSFOGRGVF ELSDEKAASPIVPSFDMSNEGSYFFGDNAEEYDNASHHHHHHfSEO ID NO :33)

ATGACATTGAACATGCTGTTGGGGCTGAAGTGGGTTTTCTTTGTTGTTTTTTATCA AGGTGTGCATTGTGAGGTGCAGCTTGTTGAGTCTGGTGGAGGATTGGTGCAGCCT AAAGGGTCATTGAAACTCTCATGTGCAGCCTCTGGATTAACCTTCAATATCTACG CCATGAACTGGGTCCGCCAGGCTCCAGGAAAGGGTTTGGAATGGGTTGCTCGCA TAAGAAATAAAAGTAATAATTATGCAACATATTATGCCGATTCAGTGAAAGACA GGTTCACCATCTCCAGAGATGATTCACAAAGCTTGCTCTATCTGCAAATGAACAA CTTGAAAACTGAGGACACAGCCATGTATTACTGTGTGGGACGGGACTGGTTTGAT TACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCAGCCAAAACGAAGGGCCCA TCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCC TGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTC AGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGA CTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGA CCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGG GGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCC CGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAG GTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAG CCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTC CTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAA GGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA GAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAG GTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGT GGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGG ACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTG GCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCAC TACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGTAGCGAGGATACTC AACCACCTGCACCGACACTCATAGGTGATGTAAATGCCGATGGAAAGATTGACT CTACAGACCTTACATTATTAAAAAGGTATTTGCTAAGAAGTGCAACGCTCACAGA AGAGAAAATTTTAAATGCGGATACAGACGGAAACGGCACGGTTAATTCAACTGA CTTAAATTATCTGAAAAAATACATATTAAGGGTTATATCTGTATTTCCGGCAGAG GGCAATAAGCCCCCGACTCCGACTCCAACAAAAACACCTGTGGCAACTCCGTCA CCAACACAACCACTGTTTACACCCAGCTTTAAAGATGTAACGGCTAGTATGGCGT CCCAAGGCACCAAACGGTCTTACGAACAGATGGAGACTGATGGAGAACGCCAGA ATGCCACTGAAATCAGAGCATCCGTCGGAAAAATGATTGGTGGAATTGGACGAT TCTACATCCAAATGTGCACCGAACTCAAACTCAGTGATTATGAGGGACGGTTGAT CCAAAACAGCTTAACAATAGAGAGAATGGTGCTCTCTGCTTTTGACGAAAGGAG AAATAAATACCTGGAAGAACATCCCAGTGCGGGGAAAGATCCTAAGAAAACTGG AGGACCTATATAC AGGAGAGTAAACGGAAAGTGGATGAGAGA ACTCATCCTTTA TGACAAAGAAGAAATAAGGCGAATCTGGCGCCAAGCTAATAATGGTGACGATGC AACGGCTGGTCTGACTCACATGATGATCTGGCATTCCAATTTGAATGATGCAACT TATCAGAGGACAAGAGCTCTTGTTCGCACCGGAATGGATCCCAGGATGTGCTCTC TGATGCAAGGTTCAACTCTCCCTAGGAGGTCTGGAGCCGCAGGTGCTGCAGTCAA AGGAGTTGGAACAATGGTGATGGAATTGGTCAGGATGATCAAACGTGGGATCAA TGATCGGAACTTCTGGAGGGGTGAGAATGGACGAAAAACAAGAATTGCTTATGA AAGAATGTGCAACATTCTCAAAGGGAAATTTCAAACTGCTGCACAAAAAGCAAT GATGGATCAAGTGAGAGAGAGCCGGAACCCAGGGAATGCTGAGTTCGAAGATCT CACTTTTCTAGCACGGTCTGCACTCATATTGAGAGGGTCGGTTGCTCACAAGTCC TGCCTGCCTGCCTGTGTGTATGGACCTGCCGTAGCCAGTGGGTACGACTTTGAAA GAGAGGGATACTCTCTAGTCGGAATAGACCCTTTCAGACTGCTTCAAAACAGCCA AGTGTACAGCCTAATCAGACCAAATGAGAATCCAGCACACAAGAGTCAACTGGT GTGGATGGCATGCCATTCTGCCGCATTTGAAGATCTAAGAGTATTAAGCTTCATC AAAGGGACGAAGGTGCTCCCAAGAGGGAAGCTTTCCACTAGAGGAGTTCAAATT GCTTCCAATGAAAATATGGAGACTATGGAATCAAGTACACTTGAACTGAGAAGC AGGTACTGGGCCATAAGGACCAGAAGTGGAGGAAACACCAATCAACAGAGGGC ATCTGCGGGCCAAATCAGCATACAACCTACGTTCTCAGTACAGAGAAATCTCCCT TTTGACAGAACAACCATTATGGCAGCATTCAATGGGAATACAGAGGGAAGAACA TCTGACATGAGGACCGAAATCATAAGGATGATGGAAAGTGCAAGACCAGAAGAT GTGTCTTTCCAGGGGCGGGGAGTCTTCGAGCTCTCGGACGAAAAGGCAGCGAGC CCGATCGTGCCTTCCTTTGACATGAGTAATGAAGGATCTTATTTCTTCGGAGACA ATGCAGAGGAGTACGACAATGCTAGCCACCATCACCATCACCATTAG(SEQ ID NO :34) [mAnti-Langerin2G3H-LV-hIgG4H-C-Flex-vl-FluNP-ls-6xHis] [NP-l s shown in double underline; Flex-vl shown in single underline]

EVQLVESGGGLVQP GSLKLSCAASGLTFNIYAMNWVRQAPGKGLEWVARIRNKSN

NYATYYADSVKDRFTISRDDSQSLLYLQMNNLKTEDTAMYYCVGRDWFDYWGQG

TLVTVSAAKTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPP CPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVH NA TKPREEQFNSTYRVVSVLTVLHQDWLNG EY CKVSNKGLPSSIEKTISKAKGQ PREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWOEGNVFSCSVMHEALHNHYTOKSLSLSLGKASQTPTNTI SVTPTNNSTPTNNSNP PNPASMASOGTKRSYEOMETGGERODATEIRASVGRMIGG IGRFYIOMCTELKLSDYDGRLIONSITIERMVLSAFDERRNKYLEEHPSAGKDPKKTG GPIYRRVDGKWMRELILYD EEIRRVWROANNGEDATAGLTHIMIWHSNLNDATYO RTRALVRTGMDPRMCSLMOGSTLPRRSGAAGAAV GVGTIAMELIRMI RGINDRN FWRGENGRRTRVAYERMCNILKGKFOTAAORAMMDOVRESRNPGNAEIEDLIFLAR SALILRGSVAHKSCLPACVYGLAVASGHDFEREGYSLVGIDPFKLLONSOVVSLMRP NENPAHKSOLVWMACHSAAFEDLRVSSFIRGK VIPRGKLSTRGVOIASNENVETMD SNTLELRSRYWAIRTRSGGNTNOOKASAGOISVOPTFSVORNLPFERATVMAAFSGN NEGRTSDMRTEVIRMMESAKPEDLSFOGRGVFELSDEKATNPIVPSFDMSNEGSYFF GDNAEEYDSASHHHHHHiSEO ID NO :35)

ATGACATTGAACATGCTGTTGGGGCTGAAGTGGGTTTTCTTTGTTGTTTTTTATCA AGGTGTGCATTGTGAGGTGCAGCTTGTTGAGTCTGGTGGAGGATTGGTGCAGCCT AAAGGGTCATTGAAACTCTCATGTGCAGCCTCTGGATTAACCTTCAATATCTACG CCATGAACTGGGTCCGCCAGGCTCCAGGAAAGGGTTTGGAATGGGTTGCTCGCA TAAGAAATAAAAGTAATAATTATGCAACATATTATGCCGATTCAGTGAAAGACA GGTTCACCATCTCCAGAGATGATTCACAAAGCTTGCTCTATCTGCAAATGAACAA CTTGAAAACTGAGGACACAGCCATGTATTACTGTGTGGGACGGGACTGGTTTGAT TACTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCAGCCAAAACGAAGGGCCCA TCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCC TGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTC AGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGA CTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGA CCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAG TTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGG GGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCC CGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAG GTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAG CCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTC CTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAA GGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA GAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAG GTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGT GGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGG ACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTG GCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCAC TACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGTCAGACCCCCACCA ACACCATCAGCGTGACCCCCACCAACAACAGCACCCCCACCAACAACAGCAACC CCAAGCCCAACCCCGCTAGTATGGCGTCTCAAGGCACCAAACGATCATATGAAC AAATGGAGACTGGTGGGGAGCGCCAGGATGCCACAGAAATCAGAGCATCTGTCG GAAGAATGATTGGTGGAATCGGGAGATTCTACATCCAAATGTGCACTGAACTCA AACTCAGTGATTATGATGGACGACTAATCCAGAATAGCATAACAATAGAGAGGA TGGTGCTTTCTGCTTTTGATGAGAGAAGAAATAAATACCTAGAAGAGCATCCCAG TGCTGGGAAGGACCCTAAGAAAACAGGAGGACCCATATATAGAAGAGTAGACG GAAAGTGGATGAGAGAACTCATCCTTTATGACAAAGAAGAAATAAGGAGAGTTT GGCGCCAAGCAAACAATGGCGAAGATGCAACAGC AGGTCTTACTCATATCATGA TTTGGCATTCCAACCTGAATGATGCCACATATCAGAGAACAAGAGCGCTTGTTCG CACCGGAATGGATCCCAGAATGTGCTCTCTAATGCAAGGTTCAACACTTCCCAGA AGGTCTGGTGCCGCAGGTGCTGCGGTGAAAGGAGTTGGAACAATAGCAATGGAG TTAATCAGAATGATCAAACGTGGAATCAATGACCGAAATTTCTGGAGGGGTGAA AATGGACGAAGGACAAGGGTTGCTTATGAAAGAATGTGCAATATCCTCAAAGGA AAATTTCAAACAGCTGCCCAGAGGGCAATGATGGATCAGGTAAGAGAAAGTCGA AACCCAGGAAACGCTGAGATTGAAGACCTCATTTTCCTGGCACGGTCAGCACTCA TTCTGAGGGGATCAGTTGCACATAAATCCTGCCTGCCTGCTTGTGTGTATGGGCT TGCAGTAGCAAGTGGGCATGACTTTGAAAGGGAAGGGTACTCACTGGTCGGGAT AGACCCATTCAAATTACTCCAAAACAGCCAAGTGGTCAGCCTGATGAGACCAAA TGAAAACCCAGCTCACAAGAGTCAATTGGTGTGGATGGCATGCCACTCTGCTGCA TTTGAAGATTTAAGAGTATCAAGTTTCATAAGAGGAAAGAAAGTGATTCCAAGA GGAAAGCTTTCCACAAGAGGGGTCCAGATTGCTTCAAATGAGAATGTGGAAACC ATGGACTCCAATACCCTGGAACTGAGAAGCAGATACTGGGCCATAAGGACCAGG AGTGGAGGAAATACCAATCAACAAAAGGCATCCGCAGGCCAGATCAGTGTGCAG CCTACATTCTCAGTGCAGCGGAATCTCCCTTTTGAAAGAGCAACCGTTATGGCAG CATTCAGCGGGAACAATGAAGGACGGACATCCGACATGCGAACAGAAGTTATAA GAATGATGGAAAGTGCAAAGCCAGAAGATTTGTCCTTCCAGGGGCGGGGAGTCT TCGAGCTCTCGGACGAAAAGGCAACGAACCCGATCGTGCCTTCCTTTGACATGAG TAATGAAGGGTCTTATTTCTTCGGAGACAATGCAGAGGAGTATGACAGTGCTAGC CACCATCACCATCACCATTGA(SEQ ID NO :36)

[mAnti-LOX-115C4H-LV-hIgG4H-C-Dockerin-v2-Flexx-vl] [Flexx-vl shown in double underline; Dockerin-v2 shown in single underline]

EIQLQQTGPELVKPGASV ISCKASGYPFTDYIMVWVKQSHGKSLEWIGNISPYYGTT NYNLKFKGKATLTVDKSSSTAYMQLNSLTSEDSAVYYCARSPNWDGAWFAHWGQ GALVTVSAAKTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVD RVESKYGPPC PPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEOFNSTYRVVSVLTVLHQDWLNG EYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKASSEDTQ PPAPTLIGDVNADGKIDSTDLTLLKRYLLRSATLTEEKILNADTDGNGTVNSTDLNYL KKY1LRVISVFPAEGNKPPTPTPTKTPVATPSPTQPLFTPSFKDVTASPSETPEEPIPTD T PSDEPTPSDEPTPSDEPTPSDEPTPSDEPTPSDEPTPSDEPTPSETPEEPTPTTTPTPTP ST TPTSGSGGSGGSGGGGGGGGGTVPTSPTPTPTSKPTSTPAPTEIEEPTASrSEO ID NO :37)

ATGGGAGGGATCTGGATCTTTCTCTTCCTCCTGTCAGGAACTGCAGGTGCCCACT CTGAGATCCAGCTGCAGCAGACTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAG TGAAGATATCCTGCAAGGCTTCTGGTTATCCATTCACTGACTACATCATGGTCTG GGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGAAATATTAGTCCTTA CTATGGTACTACTAACTACAATCTGAAGTTCAAGGGCAAGGCCACATTGACTGTA GACAAATCTTCCAGCACAGCCTACATGCAGCTCAACAGTCTGACATCTGAGGACT CTGCAGTCTATTACTGTGCAAGATCCCCTAACTGGGACGGGGCCTGGTTTGCTCA CTGGGGCCAAGGGGCTCTGGTCACTGTCTCTGCAGCCAAAACAAAGGGCCCATC CGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTG GGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAG GCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACT CTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACC TACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTT GAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGGGG GACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCG GACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGT CCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCC GCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCT GCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGG CCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA GCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGT CAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGG GAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGC AGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTA CACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGTAGCGAGGATACTCA ACCACCTGC ACCGACACTC ATAGGTGATGTAAATGCCGATGGAAAGATTGACTCT ACAGACCTTACATTATTAAAAAGGTATTTGCTAAGAAGTGCAACGCTCACAGAA GAGAAAATTTTAAATGCGGATACAGACGGAAACGGCACGGTTAATTCAACTGAC TTAAATTATCTGAAAAAATACATATTAAGGGTTATATCTGTATTTCCGGCAGAGG GCAATAAGCCCCCGACTCCGACTCCAACAAAAACACCTGTGGCAACTCCGTCAC CAACACAACCACTGTTTACACCCAGCTTTAAAGATGTAACGGCTAGTCCGTCAGA GACACCTGAGGAGCCGATACCGACGGATACACCATCAGATGAACCGACACCGTC AGACGAGCCGACACCATCTGACGAACCAACACCGTCAGACGAGCCAACGCCATC TGACGAACCGACACCGTCTGATGAGCCAACACCATCTGATGAACCGACTCCGTC AGAGACACCTGAGGAGCCGACACCGACTACTACACCGACACCAACACCGTCGAC AACGCCTACAAGTGGCAGCGGRGGCAGTGGTGGAAGCGGTGGTGGCGGCGGAG GTGGTGGAGGAACTGTACCTACATCTCCAACACCGACACCGACATCTAAACCGA CGTCTACACCTGCACCGACAGAAATCGAAGAGCCTACAGCTAGCTGA(SEQ ID NO :38) [mAnti-LOX-115C4H-LV-hIgG4H-C-Dockerin-v2-Flexx-v2] [Flexx-v2 shown in double underline; Dockerin-v2 shown in single underline]

EIQLQQTGPELVKPGASVKISCKASGYPFTDYIMVWVKQSHGKSLEWIGNISPYYGTT NYNLKFKGKATLTVD SSSTAYMQLNSLTSEDSAVYYCARSPNWDGAWFAHWGQ GALVTVSAAKTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPC PPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE

VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK

GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV

LDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKASSEDTQ PPAPTLIGDVNADGKIDSTDLTLLKRYLLRSATLTEEKILNADTDGNGTVNSTDLNYL

KKYILRVISVFPAEGNKPPTPTPTKTPVATPSPTQPLFTPSFKDVTASDEPIPTDTP SDEP TPSDEPTPSDEPTPSDEPTPSDEPTPSETPEEPIPTDTPSDEPTPSDEPTPSDEPTPSDE PTP SDEPTPSETPEEPIPTDTPSDEPTPSDEPTPSDEPTPSDEPTPSDEPTASiSEO ID NO :39) ATGGGAGGGATCTGGATCTTTCTCTTCCTCCTGTCAGGAACTGCAGGTGCCCACT CTGAGATCCAGCTGCAGCAGACTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAG TGAAGATATCCTGCAAGGCTTCTGGTTATCCATTCACTGACTACATCATGGTCTG GGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGAAATATTAGTCCTTA CTATGGTACTACTAACTACAATCTGAAGTTCAAGGGCAAGGCCACATTGACTGTA GACAAATCTTCCAGCACAGCCTACATGCAGCTCAACAGTCTGACATCTGAGGACT CTGCAGTCTATTACTGTGCAAGATCCCCTAACTGGGACGGGGCCTGGTTTGCTCA CTGGGGCCAAGGGGCTCTGGTCACTGTCTCTGCAGCCAAAACAAAGGGCCCATC CGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTG GGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAG GCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACT CTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACC TACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTT GAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGGGG GACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCG GACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGT CCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCC GCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCT GCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGG CCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA GCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGT CAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGG GAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGC AGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTA CACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGTAGCGAGGATACTCA ACCACCTGCACCGACACTCATAGGTGATGTAAATGCCGATGGAAAGATTGACTCT ACAGACCTTACATTATTAAAAAGGTATTTGCTAAGAAGTGCAACGCTCACAGAA GAGAAAATTTTAAATGCGGATACAGACGGAAACGGCACGGTTAATTCAACTGAC TTAAATTATCTGAAAAAATACATATTAAGGGTTATATCTGTATTTCCGGCAGAGG GCAATAAGCCCCCGACTCCGACTCCAACAAAAACACCTGTGGCAACTCCGTCAC CAACACAACCACTGTTTACACCCAGCTTTAAAGATGTAACGGCTAGTGACGAACC AATACCAACGGATACACCATCAGATGAACCGACACCGTCAGACGAGCCAACGCC ATCTGACGAACCGACACCGTCTGATGAGCCAACACCGTCAGATGAACCGACTCC GTCAGAGACACCTGAGGAGCCGATACCGACGGATACACCATCAGATGAACCGAC ACCATCAGACGAGCCAACGCCATCTGATGAACCAACACCGTCTGATGAGCCAAC ACCATCTGATGAACCGACTCCGTCAGAGACACCTGAGGAGCCGATACCGACGGA TACACCATCAGATGAACCGACACCGTCAGACGAGCCAACGCCATCTGACGAACC AACACCGTCTGATGAGCCAACACCGTCAGATGAACCGACTGCTAGCTGA(SEQ ID NO :40) [mAnti-LOX-115C4H-LV-hIgG4H-C-FluHAl-ls] [FluHAl -l s shown in double underline] EIQLQQTGPELVKPGASVKISCKASGYPFTDYIMVWVKQSHGKSLEWIGNISPYYGTT NYNLKFKGKATLTVDKSSSTAYMQLNSLTSEDSAVYYCARSPNWDGAWFAHWGQ GALVTVSAA TKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPC PPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALFlNHYTQ SLSLSLGKASrnLCI GYHANNSTDTVDTVLEKNVTVTHSVNLLEDKHNGKLCKLRGVAPLHLGKCNIAGW ILGNPECESLSTASSWSYIVETPSSDNGTCYPGDFIDYEELREOLSSVSSFERFEIFP TS SWPNHDSNKGVTAACPHAGAKSFYKNLIWLVKKGNSYPKLS SYINDKGKEVLVL WGIHHPSTSADOOSLYONADTYVFVGSSRYSKKFKPEIAIRPKVRDOEGRMNYYWT LVEPGDKITFEATGNLVVPRYAFAMERNAGSGIIISDTPVHDCNTTCOTPKGAINTSLP FONIHPITIGKCPKYVKSTKLRLAHHHHHHiSEO ID NO :41 )

[00185] This shows an example of a HAl-1 antigen module fused to directly H chain C-terminus.

ATGGGAGGGATCTGGATCTTTCTCTTCCTCCTGTCAGGAACTGCAGGTGCCCACT CTGAGATCCAGCTGCAGCAGACTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAG TGAAGATATCCTGCAAGGCTTCTGGTTATCCATTCACTGACTACATCATGGTCTG GGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGAAATATTAGTCCTTA CTATGGTACTACTAACTACAATCTGAAGTTCAAGGGCAAGGCCACATTGACTGTA GACAAATCTTCCAGCACAGCCTACATGCAGCTCAACAGTCTGACATCTGAGGACT CTGCAGTCTATTACTGTGCAAGATCCCCTAACTGGGACGGGGCCTGGTTTGCTCA CTGGGGCCAAGGGGCTCTGGTCACTGTCTCTGCAGCCAAAACAAAGGGCCCATC CGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTG GGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAG GCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACT CTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACC TACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTT GAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGGGG GACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCG GACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGT CC AGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCC AAGACAAAGCC GCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCT GCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGG CCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA GCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGT CAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGG GAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGC AGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTA CACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGCGACACATTATGTATA GGTTATCATGCGAACAATTCAACAGACACTGTAGACACAGTACTAGAAAAGAAT GTAACAGTAACACACTCTGTTAACCTTCTAGAAGACAAGCATAACGGGAAACTA TGCAAACTAAGAGGGGTAGCCCCATTGCATTTGGGTAAATGTAACATTGCTGGCT GGATCCTGGGAAATCCAGAGTGTGAATCACTCTCCACAGCAAGCTCATGGTCCTA CATTGTGGAAACACCTAGTTCAGACAATGGAACGTGTTACCCAGGAGATTTCATC GATTATGAGGAGCTAAGAGAGCAATTGAGCTCAGTGTCATCATTTGAAAGGTTTG AGATATTCCCCAAGACAAGTTCATGGCCCAATCATGACTCGAACAAAGGTGTAA CGGCAGCATGTCCTCATGCTGGAGCAAAAAGCTTCTACAAAAATTTAATATGGCT AGTTAAAAAAGGAAATTCATACCCAAAGCTCAGCAAATCCTACATTAATGATAA AGGGAAAGAAGTCCTCGTGCTATGGGGCATTCACCATCCATCTACTAGTGCTGAC CAACAAAGTCTCTATCAGAATGCAGATACATATGTTTTTGTGGGGTCATCAAGAT ACAGCAAGAAGTTCAAGCCGGAAATAGCAATAAGACCCAAAGTGAGGGATCAA GAAGGGAGAATGAACTATTACTGGACACTAGTAGAGCCGGGAGACAAAATAAC ATTCGAAGCAACTGGAAATCTAGTGGTACCGAGATATGCATTCGCAATGGAAAG AAATGCTGGATCTGGTATTATCATTTCAGATACACCAGTCCACGATTGCAATACA ACTTGTCAAACACCCAAGGGTGCTATAAACACCAGCCTCCCATTTCAGAATATAC ATCCGATCACAATTGGAAAATGTCCAAAATATGTAAAAAGCACAAAATTGAGAC TGGCCCATCACCATCACCATCACTGA(SEQ ID NO :42)

[manti-Dectin_l_15E2.5_H-LV-hIgG4H-C-FluHAl-ls-6xHis] [FluHAl-ls shown in double underline]

QVQLQQSGAELARPGASV MSCKASGYTFTTYTMHWVKQRPGQGLEWIGYINPSSG YTNYNQKFKDKATLTADKSSSTASMQLSSLTSEDSAVYYCARERAVLVPYAMDYW GQGTSVTVSSAKTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNT VDKRVESKYGPP CPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSRLTVDKSRWOEGNVFSCSVMHEALHNHYTOKSLSLSLGKASDTLCI GYHANNSTDTVDTVLEKNVTVTHSVNLLEDKHNGKLCKLRGVAPLHLGKCNIAGW ILGNPECESLSTASSWSYIVETPSSDNGTCYPGDFIDYEELREQLSSVSSFERFEIFPKT S SWPNHDSNKGVTAACPHAGAKSFYKNLIWLVK GNSYPKLS SYI DKGKEVLVL WGIHHPSTSADOOSLYONADTYVFVGSSRYSKKFKPEIAIRPKVRDOEGRMNYYWT LVEPGDKITFEATGNLVVPRYAFAMERNAGSGIIISDTPVHDCNTTCOTPKGAINTSLP FONIHPITIGKCPKYVKSTKLRLAHHHHHHiSEO ID NO :43)

[00186] This shows an example of a HAl -1 antigen module fused directly to H chain C -terminus. ATGGAAAGGC ACTGGATCTTTCTACTCCTGTTGTC AGTAACTGC AGGTGTCC ACT CCCAGGTCCAGCTGCAGCAGTCTGGGGCTGAACTGGCAAGACCTGGGGCCTCAG TGAAGATGTCCTGCAAGGCTTCTGGCTACACCTTTACTACCTACACTATGCACTG GGTAAAACAGAGGCCTGGACAGGGTCTGGAATGGATTGGATACATTAATCCTAG CAGTGGTTATACTAATTACAATCAGAAGTTCAAGGACAAGGCCACATTGACTGC AGACAAATCCTCCAGCACAGCCTCCATGCAACTGAGCAGCCTGACATCTGAGGA CTCTGCAGTCTATTACTGTGCAAGAGAGAGGGCGGTATTAGTCCCCTATGCTATG GACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCAGCCAAAACAAAGGGC CCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCG CCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAA CTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGA AGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGA GAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGA AGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATC TCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCC GAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACC GTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAAC AAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAAC CAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGG AGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACTCCGACGGCTCCTTCTTCCTCTAC AGCAGGCTAACCGTGGACAAGAGCAG GTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGCGACACATTAT GTATAGGTTATCATGCGAACAATTCAACAGACACTGTAGACACAGTACTAGAAA AGAATGTAACAGTAACACACTCTGTTAACCTTCTAGAAGACAAGCATAACGGGA AACTATGCAAACTAAGAGGGGTAGCCCC ATTGCATTTGGGTAAATGTAACATTGC TGGCTGGATCCTGGGAAATCCAGAGTGTGAATCACTCTCCACAGCAAGCTCATGG TCCTACATTGTGGAAACACCTAGTTCAGACAATGGAACGTGTTACCCAGGAGATT TCATCGATTATGAGGAGCTAAGAGAGCAATTGAGCTCAGTGTCATCATTTGAAAG GTTTGAGATATTCCCCAAGACAAGTTCATGGCCCAATCATGACTCGAACAAAGGT GTAACGGCAGCATGTCCTCATGCTGGAGCAAAAAGCTTCTACAAAAATTTAATAT GGCTAGTTAAAAAAGGAAATTCATACCCAAAGCTCAGCAAATCCTACATTAATG ATAAAGGGAAAGAAGTCCTCGTGCTATGGGGCATTCACCATCCATCTACTAGTGC TGACCAACAAAGTCTCTATCAGAATGCAGATACATATGTTTTTGTGGGGTCATCA AGATACAGCAAGAAGTTCAAGCCGGAAATAGCAATAAGACCCAAAGTGAGGGA TCAAGAAGGGAGAATGAACTATTACTGGACACTAGTAGAGCCGGGAGACAAAAT AACATTCGAAGCAACTGGAAATCTAGTGGTACCGAGATATGCATTCGCAATGGA AAGAAATGCTGGATCTGGTATTATCATTTCAGATACACCAGTCCACGATTGCAAT ACAACTTGTCAAACACCCAAGGGTGCTATAAACACCAGCCTCCCATTTCAGAATA TACATCCGATCACAATTGGAAAATGTCCAAAATATGTAAAAAGCACAAAATTGA GACTGGCCCATCACCATCACCATCACTGA(SEQ ID NO :44)

[manti-CD40_12E12.3F3_H-LV-hIgG4H-C-FluHAl-ls-6xHis] [FluHAl-ls is shown in double underline]

EV LVESGGGLVQPGGSLKLSCATSGFTFSDYYMYWVRQTPEKRLEWVAYINSGGG STYYPDTVKGRFTISRDNAKNTLYLQMSRLKSEDTAMYYCARRGLPFHAMDYWGQ GTSVTVSSAKTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPP CPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQ PREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWOEGNVFSCSVMHEALHNHYTOKSLPLSLGKASDTLCIGY HANNSTDTVDTVLEKNVTVTHSVNLLEDKHNGKLC LRGVAPLHLGKCNIAGWILG NPECESLSTASSWSYIVETPSSDNGTCYPGDFIDYEELREOLSSVSSFERFEIFPKTSSW PNHDSNKGVTAACPHAGAKSFYKNLIWLVKKGNSYPKLSKSYINDKGKEVLVLWGI HHPSTSADOOSLYONADTYVFVGSSRYSKKFKPEIAIRPKVRDOEGRMNYYWTLVE PGDKITFEATGNLVVPRYAFAMERNAGSGIIISDTPVHDCNTTCOTPKGAINTSLPFON IHPITIGKCPKYVKSTKLRLAHHHHHHCSEO ID NO :45)

[00187] This shows an example of a HAl -1 antigen module fused directly to H chain C-terminus. ATGAACTTGGGGCTCAGCTTGATTTTCCTTGTCCTTGTTTTAAAAGGTGTCCAGTG TGAAGTGAAGCTGGTGGAGTCTGGGGGAGGCTTAGTGCAGCCCGGAGGGTCCCT GAAACTCTCCTGTGCAACCTCTGGATTCACTTTCAGTGACTATTACATGTATTGGG TTCGCCAGACTCCAGAGAAGAGGCTGGAGTGGGTCGCATACATTAATTCTGGTG GTGGTAGCACCTATTATCCAGACACTGTAAAGGGCCGATTCACCATCTCCAGAGA CAATGCCAAGAACACCCTGTACCTGCAAATGAGCCGGCTGAAGTCTGAGGACAC AGCCATGTATTACTGTGCAAGACGGGGGTTACCGTTCCATGCTATGGACTATTGG GGTCAAGGAACCTCAGTCACCGTCTCCTCAGCCAAAACGAAGGGCCCATCCGTCT TCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCC CTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACT CCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACA CCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGT CCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGGGGGACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAG TTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGG GAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACC AGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCC CGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCAC AGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCC TGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCG ACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGG AGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACAC ACAGAAGAGCCTCCCCCTGTCTCTGGGTAAAGCTAGCGACACATTATGTATAGGT TATCATGCGAACAATTCAACAGACACTGTAGACACAGTACTAGAAAAGAATGTA ACAGTAACACACTCTGTTAACCTTCTAGAAGACAAGCATAACGGGAAACTATGC AA ACTAAG AGGGGT AGC C C C ATTGC ATTTGGGTA A ATGTAAC ATTGCTGGCTGG ATCCTGGGAAATCC AG AGTGTGAATCACTCTCCACAGCAAGCTCATGGTCCTAC A TTGTGGAAACACCTAGTTCAGACAATGGAACGTGTTACCCAGGAGATTTCATCGA TTATGAGGAGCTAAGAGAGCAATTGAGCTCAGTGTCATCATTTGAAAGGTTTGAG ATATTCCCCAAGACAAGTTCATGGCCCAATCATGACTCGAACAAAGGTGTAACG GCAGCATGTCCTCATGCTGGAGCAAAAAGCTTCTACAAAAATTTAATATGGCTAG TTAAAAAAGGAAATTC ATACCC AAAGCTC AGC AAATCCTAC ATTAATGATAAAG GGAAAGAAGTCCTCGTGCTATGGGGCATTCACCATCCATCTACTAGTGCTGACCA ACAAAGTCTCTATCAGAATGCAGATACATATGTTTTTGTGGGGTCATCAAGATAC AGCAAGAAGTTCAAGCCGGAAATAGCAATAAGACCCAAAGTGAGGGATCAAGA AGGGAGAATGAACTATTACTGGACACTAGTAGAGCCGGGAGACAAAATAACATT CGAAGCAACTGGAAATCTAGTGGTACCGAGATATGCATTCGCAATGGAAAGAAA TGCTGGATCTGGTATTATCATTTCAGATACACCAGTCCACGATTGCAATACAACT TGTCAAACACCCAAGGGTGCTATAAACACCAGCCTCCCATTTCAGAATATACATC CGATCACAATTGGAAAATGTCCAAAATATGTAAAAAGCACAAAATTGAGACTGG CCCATCACCATCACCATCACTGA(SEQ ID NO :46)

[6xHis-CthermoCohesin-FluHAl-ls-6xHis] [FluHAl-ls is shown in double underline; CthermoCohesin is shown in single underline]

MGSSHHHHHHSSGLVPRGSHMASMDLDAVRIKVDTVNAKPGDTVNIPVRFSGIPSK GIANCDFVYSYDPNVLEI1EIKPGELIVDPNPTKSFDTAVYPDRKMIVFLFAEDSGTGA YAITKDGVFATIVAKVKEGAPNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGD TTEPATPTTPVTTPTTTDDLDAASDTLCIGYHANNSTDTVDTVLEKNVTVTHSVNLLE DKHNGKLCKLRGVAPLHLGKCNIAGWILGNPECESLSTASSWSYIVETPSSDNGTCY PGDFIDYEELREOLSSVSSFERFEIFPKTSSWPNHDSNKGVTAACPHAGAKSFYKNLI WLVKKGNSYPKLSKSYINDKGKEVLVLWGIHHPSTSADOOSLYONADTYVFVGSSR YSKKFKPEIAIRPKVRDOEGRMNYYWTLVEPGD ITFEATGNLVVPRYAFAMERNA GSGIIISDTPVHDCNTTCOTPKGAINTSLPFONIHPITIGKCPKYVKSTKLRLAHHHHHH

(SEQ ID NO :47)

[00188] This shows a HAl -1 antigen module which can be attached to a DC- targeting vaccine bearing a dockerin domain.

ATGGGCAGCAGCCATCATCATCATCATCACAGCAGCGGCCTGGTGCCGCGCGGC AGCCATATGGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTA AATGCAAAACCGGGAGACACAGTAAATATACCTGTAAGATTCAGTGGTATACCA TCCAAGGGAATAGCAAACTGTGACTTTGTATACAGCTATGACCCGAATGTACTTG AGATAATAGAGATAAAACCGGGAGAATTGATAGTTGACCCGAATCCTACCAAGA GCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTATTCCTGTTTGCGGA AGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTACGAT AGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGT AGAAGTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTT TGACGGTGGAGTAAATGTTGGAGATACAACAGAACCTGCAACACCTACAACACC TGTAACAACACCGACAACAACAGATGATCTAGATGCAGCTAGCGACACATTATG TATAGGTTATCATGCGAACAATTCAACAGACACTGTAGACACAGTACTAGAAAA GAATGTAACAGTAACACACTCTGTTAACCTTCTAGAAGACAAGCATAACGGGAA ACTATGCAAACTAAGAGGGGTAGCCCCATTGCATTTGGGTAAATGTAACATTGCT GGCTGGATCCTGGGAAATCCAGAGTGTGAATCACTCTCCACAGCAAGCTCATGGT CCTACATTGTGGAAACACCTAGTTCAGACAATGGAACGTGTTACCCAGGAGATTT CATCGATTATGAGGAGCTAAGAGAGCAATTGAGCTCAGTGTCATCATTTGAAAG GTTTGAGATATTCCCCAAGACAAGTTCATGGCCCAATCATGACTCGAACAAAGGT GTAACGGCAGCATGTCCTCATGCTGGAGCAAAAAGCTTCTACAAAAATTTAATAT GGCTAGTTAAAAAAGGAAATTCATACCCAAAGCTCAGCAAATCCTACATTAATG ATAAAGGGAAAGAAGTCCTCGTGCTATGGGGCATTCACCATCCATCTACTAGTGC TGACCAACAAAGTCTCTATCAGAATGCAGATACATATGTTTTTGTGGGGTCATCA AGATACAGCAAGAAGTTCAAGCCGGAAATAGCAATAAGACCCAAAGTGAGGGA TCAAGAAGGGAGAATGAACTATTACTGGACACTAGTAGAGCCGGGAGACAAAAT AACATTCGAAGCAACTGGAAATCTAGTGGTACCGAGATATGCATTCGCAATGGA AAGAAATGCTGGATCTGGTATTATCATTTCAGATACACCAGTCCACGATTGCAAT ACAACTTGTCAAACACCCAAGGGTGCTATAAACACCAGCCTCCCATTTCAGAATA TACATCCGATCACAATTGGAAAATGTCCAAAATATGTAAAAAGCACAAAATTGA GACTGGCCCATCACCATCACCATCACTGA(SEQ ID NO :48)

[mAnti-LOX-115C4H-LV-hIgG4H-C-Flex-vl-FluHAl-ls-6xHis] [FluHAl -ls is shown in double underline; Flex-vl is shown in single underline]

EIQLQQTGPELVKPGASVKISCKASGYPFTDYIMVWVKQSHGKSLEWIGNISPYYGTT NYNLKFKGKATLTVDKSSSTAYMQLNSLTSEDSAVYYCARSPNWDGAWFAHWGQ GALVTVSAAKTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVVTVPSSSLGT TYTCNVDHKPSNTKVDKRVESKYGPPC PPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG ASQTPTN TISVTPTNNSTPTNNSNP PNPASDTLCIGYHANNSTDTVDTVLEKNVTVTHSVNLLE DKHNGKLCKLRGVAPLHLGKCNIAGWILGNPECESLSTASSWSYIVETPSSDNGTCY PGDFIDYEELREOLSSVSSFERFEIFPKTSSWPNHDSNKGVTAACPHAGAKSFYKNLI WLVKKGNSYPKLSKSYINDKGKEVLVLWGIHHPSTSADOOSLYONADTYVFVGSSR YSKKFKPEIAIRPKVRDOEGRMNYYWTLVEPGDKITFEATGNLVVPRYAFAMERNA GSGIIISDTPVHDCNTTCOTPKGAINTSLPFONIHPITIGKCPKYVKST LRLAHHHHHH

(SEQ ID NO :49)

[00189] This shows an example of a HAl-1 antigen module fused to H chain

C-terminus via a flexible linker sequence.

ATGGGAGGGATCTGGATCTTTCTCTTCCTCCTGTCAGGAACTGCAGGTGCCCACT CTGAGATCCAGCTGCAGCAGACTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAG TGAAGATATCCTGCAAGGCTTCTGGTTATCCATTCACTGACTACATCATGGTCTG GGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGAAATATTAGTCCTTA CTATGGTACTACTAACTACAATCTGAAGTTCAAGGGCAAGGCCACATTGACTGTA GACAAATCTTCCAGCACAGCCTACATGCAGCTCAACAGTCTGACATCTGAGGACT CTGCAGTCTATTACTGTGCAAGATCCCCTAACTGGGACGGGGCCTGGTTTGCTCA CTGGGGCCAAGGGGCTCTGGTCACTGTCTCTGCAGCCAAAACAAAGGGCCCATC CGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTG GGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAG GCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACT CTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACC TACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTT GAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGGGG GACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCG GACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGT CCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCC GCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCT GCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGG CCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA GCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGT CAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGG GAGAGC A ATGGGC AGCCGGAGAAC AACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGC AGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTA CACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGTCAGACCCCCACCAAC ACCATCAGCGTGACCCCCACCAACAACAGCACCCCCACCAACAACAGCAACCCC AAGCCCAACCCCGCTAGCGACACATTATGTATAGGTTATCATGCGAACAATTCAA CAGACACTGTAGACACAGTACTAGAAAAGAATGTAACAGTAACACACTCTGTTA ACCTTCTAGAAGACAAGCATAACGGGAAACTATGCAAACTAAGAGGGGTAGCCC CATTGCATTTGGGTAAATGTAACATTGCTGGCTGGATCCTGGGAAATCCAGAGTG TGAATCACTCTCCACAGCAAGCTCATGGTCCTACATTGTGGAAACACCTAGTTCA GACAATGGAACGTGTTACCCAGGAGATTTCATCGATTATGAGGAGCTAAGAGAG CAATTGAGCTCAGTGTCATCATTTGAAAGGTTTGAGATATTCCCCAAGACAAGTT CATGGCCCAATCATGACTCGAACAAAGGTGTAACGGCAGCATGTCCTCATGCTG GAGCAAAAAGCTTCTACAAAAATTTAATATGGCTAGTTAAAAAAGGAAATTCAT ACCCAAAGCTCAGCAAATCCTACATTAATGATAAAGGGAAAGAAGTCCTCGTGC TATGGGGCATTCACCATCCATCTACTAGTGCTGACCAACAAAGTCTCTATCAGAA TGCAGATACATATGTTTTTGTGGGGTCATCAAGATACAGCAAGAAGTTCAAGCCG GAAATAGCAATAAGACCCAAAGTGAGGGATCAAGAAGGGAGAATGAACTATTA CTGGACACTAGTAGAGCCGGGAGACAAAATAACATTCGAAGCAACTGGAAATCT AGTGGTACCGAGATATGCATTCGCAATGGAAAGAAATGCTGGATCTGGTATTATC ATTTCAGATACACCAGTCCACGATTGCAATACAACTTGTCAAACACCCAAGGGTG CTATAAACACCAGCCTCCCATTTCAGAATATACATCCGATCACAATTGGAAAATG TCCAAAATATGTAAAAAGCACAAAATTGAGACTGGCCCATCACCATCACCATCA CTGA(SEQ ID NO :50)

[6xHis-Cohesin-FluHA3-lk] [FluHA3-lk is shown in double underline; Cohesin is shown in single underline]

LDITSHHHHHHDDLDAVRIKVDTVNA PGDTVRIPVRFSGIPSKGIANCDFVYSYDPN VLEIIEIEPGDIIVDPNPDKSFDTAVYPDR IIVFLFAEDSGTGAYAITKDGVFATIVAK V EGAPNGLSVI FVEVGGFANNDLVEOKTQFFDGGVNVGDTTEPATPTTPVTTPTT TDDLD AA SDTTEP ATPTTP VTTATLCLGHH A VPNGTLVKTITDDOIEVTNATEL VO S S STGKICNNPHRILDGIDCTLIDALLGDPHCDVFONETWDLFVERSKAFSNCYPYDVPD YASLRSLVASSGTLEFITEGFTWTGVTONGGSNACKRGPGSGFFSRLNWLTKSGSTY PVLNVTMPNNDNFDKLYIWGVHHPSTNOEOTSLYVOASGRVTVSTRRSOOTIIPNIGS RPWVRGLSSRISIYWTIVKPGDVLVINSNGNLIAPRGYFKMRTGKSSIMRSDAPIDTCI SECITPNGSIPNDKPFONVNKITYGACPKYVKONTLKLAiSEO ID NO :51)

[00190] This permits attachment to the DC-targeting vaccine of HA1 antigen from a H3 influenza A strain.

ATGGATCCCAAAGGATCCCTTTCCTGGAGAATACTTCTGTTTCTCTCCCTGGCTTT TGAGTTGAGCTACGGACTCGACATCACATCCCACCATCACCATCACCATGACGAT CTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAGACACA GTAAGAATACCTGTAAGATTCAGCGGTATACCATCCAAGGGAATAGCAAACTGT GACTTTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAGAACCG GGAGACATAATAGTTGACCCGAATCCTGACAAGAGCTTTGATACTGCAGTATATC CTGACAGAAAGATAATAGTATTCCTGTTTGCAGAAGACAGCGGAACAGGAGCGT ATGCAATAACTAAAGACGGAGTATTTGCTACGATAGTAGCGAAAGTAAAAGAAG GAGCACCTAACGGACTCAGTGTAATCAAATTTGTAGAAGTAGGCGGATTTGCGA AC AATGACCTTGTAGAACAGAAGAC AC AGTTCTTTGACGGTGGAGTAAATGTTG GAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAA CAGATGATCTGGATGCAGCTAGCGATACAACAGAACCTGCAACACCTACAACAC CTGTAACAACAGCAACGCTGTGCCTGGGACATCATGCGGTGCCAAACGGAACAC TAGTGAAAACAATCACAGATGATCAGATTGAAGTGACTAATGCTACTGAGCTAG TTCAGAGCTCCTCAACGGGGAAAATATGCAACAATCCTCATCGAATCCTTGATGG AATAGACTGCACACTGATAGATGCTCTATTGGGGGACCCTCATTGTGATGTTTTT CAAAATGAGACATGGGACCTTTTCGTTGAACGCAGCAAAGCTTTCAGCAACTGTT ACCCTTATGATGTGCCAGATTATGCCTCCCTTAGGTCACTAGTTGCCTCGTCAGGC ACTCTGGAGTTTATCACTGAGGGTTTCACTTGGACTGGGGTCACTCAGAATGGGG GAAGCAATGCTTGCAAAAGGGGACCTGGTAGCGGTTTTTTCAGTAGACTGAACT GGTTGACCAAATCAGGAAGCACATATCCAGTGCTGAACGTGACTATGCCAAACA ATGACAATTTTGACAAACTATACATTTGGGGGGTTCACCACCCGAGCACGAACCA AGAACAAACCAGCCTGTATGTTCAAGCATCAGGGAGAGTCACAGTCTCTACCAG GAGAAGCCAGCAAACTATAATCCCGAATATCGGGTCCAGACCCTGGGTAAGGGG TCTGTCTAGTAGAATAAGCATCTATTGGACAATAGTTAAGCCGGGAGACGTACTG GTAATTAATAGTAATGGGAACCTAATCGCTCCTCGGGGTTATTTCAAAATGCGCA CTGGGAAAAGCTCAATAATGAGGTCAGATGCACCTATTGATACCTGTATTTCTGA ATGCATCACTCCAAATGGAAGCATTCCCAATGACAAGCCCTTTCAAAACGTAAAC AAGATCACATATGGAGCATGCCCCAAGTATGTTAAGCAAAACACCCTGAAGTTG GCATGA(SEQ ID NO :52)

[Ecoli-pET28[6xHis-Cohesin-FIuHAl-lc] [FluHAl-lc is shown in double underline; Cohesin is shown in single underline]

MGSSHHHHHHSSGLVPRGSHMASMDLDAVRIKVDTVNAKPGDTVNIPVRFSGIPSK GIANCDFVYSYDPNVLEIIEIKPGELIVDPNPTKSFDTAVYPDRKMIVFLFAEDSGTGA YAITKDGVFATIVAKVKEGAPNGLSVIKFVEVGGFANNDLVEOKTQFFDGGVNVGD TTEPATPTTPVTTPTTTDDLDAASDTTEPATPTTPVTTDTICIGYHANNSTDTVDTVLE KNVTVTHSV LLEDKHNGKLCKLRGVAPLHLG CNIAGWILGNPECESLSTASSWS YIVETSSSDNGTCYPGDFIDYEELREOLSSVSSFERFEIFPKTSSWPNHDSNKGVTAAC PHAGAKSFYKNLIWLVKKGNSYPKLSKSYINDKGKEVLVLWGIHHPSTSDDOOSLY ONADAYVFVGSSRYSKKF PEIAIRPKVRDOEGRMNYYWTLVEPGDKITFEATGNL VVPRYAFAMERNAGSGIIISDTPVHDCNTTCOTPKGAI TSLPFONIOPITIG CPKYV KSTKLRLfSEO ID NO :53)

[00191] This permits attachment to the DC-targeting vaccine of HA1 antigen from a influenza A strain.

ATGGGCAGCAGCCATCATCATCATCATCACAGCAGCGGCCTGGTGCCGCGCGGC AGCCATATGGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTA AATGCAAAACCGGGAGACACAGTAAATATACCTGTAAGATTCAGTGGTATACCA TCCAAGGGAATAGCAAACTGTGACTTTGTATACAGCTATGACCCGAATGTACTTG AGATAATAGAGATAAAACCGGGAGAATTGATAGTTGACCCGAATCCTACCAAGA GCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTATTCCTGTTTGCGGA AGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTACGAT AGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGT AGAAGTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTT TGACGGTGGAGTAAATGTTGGAGATACAACAGAACCTGCAACACCTACAACACC TGTAACAACACCGACAACAACAGATGATCTAGATGCAGCTAGCGATACAACAGA ACCTGC AAC ACCTAC AACACCTGTAAC AACAGAC AC AATATGTATAGGTTATCAT GCGAACAATTCAACAGACACTGTAGACACAGTACTAGAAAAGAATGTAACAGTA ACACACTCTGTTAACCTTCTAGAAGACAAGCATAACGGGAAACTATGCAAACTA AGAGGGGTAGCCCCATTGCATTTGGGTAAATGTAACATTGCTGGCTGGATCCTGG GAAATCCAGAGTGTGAATCACTCTCCACAGCAAGCTCATGGTCCTACATTGTGGA AACATCTAGTTCAGACAATGGAACGTGTTACCCAGGAGATTTCATCGATTATGAG GAGCTAAGAGAGCAATTGAGCTCAGTGTCATCATTTGAAAGGTTTGAGATATTCC CCAAGACAAGTTCATGGCCCAATCATGACTCGAACAAAGGTGTAACGGCAGCAT GTCCTCATGCTGGAGCAAAAAGCTTCTACAAAAATTTAATATGGCTAGTTAAAAA AGGAAATTCATACCCAAAGCTCAGCAAATCCTACATTAATGATAAAGGGAAAGA AGTCCTCGTGCTATGGGGCATTCACCATCCATCTACTAGTGACGACCAACAAAGT CTCTATCAGAATGCAGATGCATATGTTTTTGTGGGGTCATCAAGATACAGCAAGA AGTTCAAGCCGGAAATAGCAATAAGACCCAAAGTGAGGGATCAAGAAGGGAGA ATGAACTATTACTGGACACTAGTAGAGCCGGGAGACAAAATAACATTCGAAGCA ACTGGAAATCTAGTGGTACCGAGATATGCATTCGCAATGGAAAGAAATGCTGGA TCTGGTATTATCATTTCAGATACACCAGTCCACGATTGCAATACAACTTGTCAAA CACCCAAGGGTGCTATAAACACCAGCCTCCCATTTCAGAATATACAGCCGATCAC AATTGGAAAATGTCCAAAATATGTGAAAAGCACAAAATTGAGACTGTGA(SEQ ID NO :54)

Ecoli-pET28[6xHis-Cohesin-FluHAb-l] [FluHAb-1 is shown in double underline; Cohesin is shown in single underline]

MGS SHHHHHHS S GLVP GSHMASMDLDAVRI VDTVNAKPGDTVNIPVRFSGIPSK GIANCDFVYSYDPNVLEIIEIKPGELIVDPNPTKSFDTAVYPDRKMIVFLFAEDSGTGA YAITKDGVFATIVAKVKEGAPNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGD TTEPATPTTPVTTPTTTDDLDAASDRICTGITSSNSPHVVKTATOGEVNVTGVIPLTTT PTKSHFANLKGTETRG LCPKCLNCTDLDVALGRPKCTGKIPSARVSILHEVRPVTSG CFPIMHDRTKIROLPNLLRGYEHIRLSTHNVINAENAPGGPYKIGTSGSCPNITNGNGF FATMAWAVPKNDKNKTATNPLTIEVPYICTEGEDOITVWGFHSDDETOMAKLYGDS KPO FTSSANGVTTHYVSOIGGFPNOTEDGGLPOSGRIVVDYMVOKSG TGTITYOR GILLPOKVWCASGRS VIKGSLPLIGEADCLHEKYGGLNKSKPYYTGEHAKAIGNCPI WVKTPLKLANGTKCSEO ID NO :55) [00192] This permits attachment to the DC-targeting vaccine of HA1 antigen from a influenza B strain.

ATGGGCAGCAGCCATCATCATCATCATCACAGCAGCGGCCTGGTGCCGCGCGGC AGCCATATGGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTA AATGCAAAACCGGGAGACACAGTAAATATACCTGTAAGATTCAGTGGTATACCA TCCAAGGGAATAGCAAACTGTGACTTTGTATACAGCTATGACCCGAATGTACTTG AGATAATAGAGATAAAACCGGGAGAATTGATAGTTGACCCGAATCCTACCAAGA GCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTATTCCTGTTTGCGGA AGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTACGAT AGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGT AGAAGTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTT TGACGGTGGAGTAAATGTTGGAGATACAACAGAACCTGCAACACCTACAACACC TGTAACAACACCGACAACAACAGATGATCTAGATGCAGCTAGCGATCGAATCTG CACTGGAATAACATCGTCAAACTCACCACATGTCGTCAAAACTGCTACTCAAGGG GAGGTCAATGTGACAGGTGTAATACCACTGACAACAACACCCACCAAATCTCAT TTTGCAAATCTCAAAGGAACAGAAACCAGGGGGAAACTATGCCCAAAATGCCTC AACTGCACAGATCTGGACGTAGCCTTGGGCAGACCAAAATGCACGGGGAAAATA CCCTCGGCAAGAGTTTCAATACTCCATGAAGTCAGACCTGTTACATCTGGGTGCT TTCCTATAATGCACGACAGAACAAAAATTAGACAGCTGCCTAACCTTCTCCGAGG ATACGAACATATCAGGTTATCAACCCATAACGTTATCAATGCAGAAAATGCACC AGGAGGACCCTACAAAATTGGAACCTCAGGGTCTTGCCCTAACATTACCAATGG AAACGGATTTTTCGCAACAATGGCTTGGGCCGTCCCAAAAAACGACAAAAACAA AACAGCAACAAATCCATTAACAATAGAAGTACCATACATTTGTACAGAAGGAGA AGACCAAATTACCGTTTGGGGGTTCCACTCTGACGACGAGACCCAAATGGCAAA GCTCTATGGGGACTCAAAGCCCCAGAAGTTCACCTCATCTGCCAACGGAGTGACC ACACATTACGTTTCACAGATTGGTGGCTTCCCAAATCAAACAGAAGACGGAGGA CTACCACAAAGTGGTAGAATTGTTGTTGATTACATGGTGCAAAAATCTGGGAAA ACAGGAACAATTACCTATCAAAGGGGTATTTTATTGCCTCAAAAGGTGTGGTGCG CAAGTGGCAGGAGCAAGGTAATAAAAGGATCCTTGCCTTTAATTGGAGAAGCAG ATTGCCTCCACGAAAAATACGGTGGATTAAACAAAAGCAAGCCTTACTACACAG GGGAACATGCAAAGGCCATAGGAAATTGCCCAATATGGGTGAAAACACCCTTGA AGCTGGCCAATGGAACCAAATGA(SEQ ID NO :56) EcoIi-pET28[6xHis-Cohesin-FIuHAl-headless-6xHis] [FluHAl -headless is shown in double underline; Cohesin is shown in single underline]

MGSSHHHHHHSSGLVPRGSHMASMDLDAVRIKVDTVNAKPGDTVNIPVRFSGIPSK GIANCDFVYSYDPNVLEIIEIKPGELIVDPNPTKSFDTAVYPDRKMIVFLFAEDSGTGA YAITKDGVFATIVAKVKEGAPNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGD TTEPATPTTPVTTPTTTDDLDAASDTTEPATPTTPVTTDTICIGYHANNSTDTVDTVLE KNVTVTHSWLLEDSHNGKLCGGGSCNTKCOTPLGAINSSLPYONIHPVTIGECPKY VRSAKLRMVTGLRNTPSIOSRGLFGAIAGFIEGGWTGMIDGWYGYHHONEOGSGYA ADOKSTONAINGITNKVNTVIEKMNIOFTAVG EFNKLEKRMENLNKKVDDGFLDI WTYNAELLVLLENERTLDFHDSNVKNLYE VKSQLKN AKEIGNGCFEFYHKCDNE CMESVRNGTYDYPKYSEESKLNREKVDGV LESMGIYOILAIYSTHHHHHHCSEO ID NO :57)

[00193] This can be used to attach to the DC-targeting vaccine 'headless' form of influenza HA, which is rich in relatively well conserved residues known to elicit protective broadly cross-reactive immunity.

ATGGGCAGCAGCCATCATCATCATCATCACAGCAGCGGCCTGGTGCCGCGCGGC AGCCATATGGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTA AATGCAAAACCGGGAGACACAGTAAATATACCTGTAAGATTCAGTGGTATACCA TCCAAGGGAATAGCAAACTGTGACTTTGTATACAGCTATGACCCGAATGTACTTG AGATAATAGAGATAAAACCGGGAGAATTGATAGTTGACCCGAATCCTACCAAGA GCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTATTCCTGTTTGCGGA AGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTACGAT AGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGT AGAAGTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTT TGACGGTGGAGTAAATGTTGGAGATACAACAGAACCTGCAACACCTACAACACC TGTAACAACACCGACAACAACAGATGATCTAGATGCAGCTAGCGATACAACAGA ACCTGCAACACCTACAACACCTGTAACAACAGACACAATATGTATAGGCTACCA TGCGAACAATTCAACCGACACTGTTGACACAGTACTCGAGAAGAATGTGACAGT GACACACTCTGTTAACCTGCTCGAAGACAGCCACAACGGAAAACTATGTGGCGG CGG ATCCTGTAAC ACGAAGTGTC AAAC ACCCCTGGGAGCTATAAAC AGC AGTCT CCCTTACCAGAATATACACCCAGTCACAATAGGAGAGTGCCCAAAATACGTCAG GAGTGCCAAATTGAGGATGGTTACAGGACTAAGGAACACTCCGTCCATTCAATC CAGAGGTCTATTTGGAGCCATTGCCGGTTTTATTGAAGGGGGATGGACTGGAATG ATAGATGGATGGTATGGTTATCATCATCAGAATGAACAGGGATCAGGCTATGCA GCGGATCAAAAAAGCACACAAAATGCCATTAACGGGATTACAAACAAGGTGAAC ACTGTTATCGAGAAAATGAACATTCAATTCACAGCTGTGGGTAAAGAATTCAAC AAATTAGAAAAAAGGATGGAAAATTTAAATAAAAAAGTTGATGATGGATTTCTG GACATTTGGACATATAATGCAGAATTGTTAGTTCTACTGGAAAATGAAAGGACTC TGGATTTCCATGACTCAAATGTGAAGAATCTGTATGAGAAAGTAAAAAGCCAAT TAAAGAATAATGCCAAAGAAATCGGAAATGGATGTTTTGAGTTCTACCACAAGT GTGACAATGAATGCATGGAAAGTGTAAGAAATGGGACTTATGATTATCCCAAAT ATTCAGAAGAGTCAAAGTTGAACAGGGAAAAGGTAGATGGAGTGAAATTGGAAT CAATGGGGATCTATCAGATTCTGGCGATCTACTCAACTCACCATCACCATCATCA TTGA(SEQ ID NO :58)

[mAnti-LOX-115C4K-LV-hIgGK-C-Flgn-l-Flgn-2] [Flgn-l -Flgn-2 is shown in double underline]

DIVLTQSPASLAVSLGQRATISCKASQSVDYDGDSYMNWFQQKPGQPPKLLIYAASN LESGIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQSNEDPFTFGSGTKLEIKRTVAA PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECASIERLSSGLRINS AKDDAAGOAIANRFTANIKGLTOASRNANDGISIAOTTEGALNEINNNLORVRELAV OSANSTNSOSDLDSIOAEITORLNEIDRVSGOTOFNGVKVLAODNTLTIOVGANDGET IDIDLKOINSOTLGLDSLNVOASOPELAEAAAKTTENPLOKIDAALAOVDALRSDLGA VONRFNSAITNLGNTVN LSEARSRIEDSDYATEVSNMSRAOILOASrSEO ID NO :59) [00194] This can be used to attach to the DC-targeting vaccine the immuno stimulatory properties of flagellin, in this example, via direct fusion to the L chain component.

ATGGAGACAGACACAATCCTGCTATGGGTGCTGCTGCTCTGGGTTCCAGGCTCCA CTGGTGACATTGTGCTGACCCAATCTCCAGCTTCTTTGGCTGTGTCTCTAGGGCAG AGGGCCACCATCTCCTGCAAGGCCAGCCAAAGTGTTGATTATGATGGTGATAGTT ATATGAACTGGTTCCAACAGAAACCAGGACAGCCACCCAAACTCCTCATCTATGC TGCATCCAATCTAGAATCTGGGATCCCAGCCAGGTTTAGTGGCAGTGGGTCTGGG ACAGACTTCACCCTCAACATCCATCCTGTGGAGGAGGAGGATGCTGCAACCTATT ACTGTCAGCAAAGTAATGAGGATCCATTCACGTTCGGCTCGGGGACAAAGCTCG AGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGA GCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCC AGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCC CAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAG CACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTATGCCTGCGA AGTC ACCCATC AGGGCCTGAGCTCGCCCGTC AC AAAGAGCTTC AACAGGGGAGA GTGTGCTAGTATCGAGCGTCTGTCTTCTGGTCTGCGTATCAACAGCGCGAAAGAC GATGCGGCAGGTCAGGCGATTGCTAACCGTTTTACCGCGAACATCAAAGGTCTG ACTCAGGCTTCCCGTAACGCTAACGACGGTATCTCCATCGCGCAGACCACTGAAG GCGCGCTGAACGAAATCAACAACAACCTGCAGCGTGTGCGTGAACTGGCGGTTC AGTCTGCTAAC AGC ACTAACTCCCAGTCTGACCTCGACTCCATCCAGGCTGAAAT CACCCAGCGCCTGAACGAAATCGACCGTGTATCCGGTCAGACTCAGTTCAACGG CGTGAAAGTCCTGGCGCAGGACAACACCCTGACCATCCAGGTTGGTGCCAACGA CGGTGAAACTATCGATATCGATCTGAAGCAGATCAACTCTCAGACCCTGGGCCTG GATTCACTGAACGTGCAGGCTAGTCAACCAGAGCTGGCGGAAGCAGCCGCTAAA ACCACCGAAAACCCGCTGCAGAAAATTGATGCCGCGCTGGCGCAGGTGGATGCG CTGCGCTCTGATCTGGGTGCGGTACAAAACCGTTTCAACTCCGCTATCACCAACT TGGGCAATACCGTAAACAACCTGTCTGAAGCGCGTAGCCGTATCGAAGATTCCG ACTACGCGACCGAAGTTTCCAACATGTCTCGCGCGCAGATTCTGCAGGCTAGCTG

A(SEQ ID NO :60)

[manti-Dectin_l_15E2.5_K-LV-hIgGK-C-Flgn-l-Flgn-2] [Flgn-l-Flgn-2 is shown in double underline] QIVLTQSPAVMSASPGEKVTITCTASSSLSYMHWFQQKPGTSPKLWLYSTSILASGVP TRFSGSGSGTSYSLTISRMEAEDAATYYCQQRSSSPFTFGSGTKLEIKRTVAAPSVFIFP PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS DSTYSL SSTLTLS ADYEKH VYACEVTHOGLSSPVTKSFNRGECASIERLSSGLRINSAKDDA AGQAIANRFTANIKGLTOASRNANDGISIAOTTEGALNEINNNLORVRELAVOSANST NSOSDLDSIOAEITORLNEIDRVSGOTOFNGVKVLAODNTLTIOVGANDGETIDIDLK OINSOTLGLDSLNVOASOPELAEAAAKTTENPLOKIDAALAOVDALRSDLGAVONRF NSAITNLGNTVNNLSEARSRIEDSDYATEVSNMSRAOILQASCSEO ID NO :61) [00195] This can be used to attach to the DC-targeting vaccine the immuno stimulatory properties of flagellin, in this example, via direct fusion to the L chain component.

ATGCATTTTCAAGTGCAGATTTTCAGCTTCCTGCTAATCAGTGCCTCAGTCATAAT GTCCAGAGGACAAATTGTTCTCACCCAGTCTCCAGCAGTCATGTCTGCATCTCCA GGGGAGAAGGTCACCATAACCTGCACTGCCAGCTCAAGTTTAAGTTACATGCACT GGTTCCAGCAGAAGCCAGGCACTTCTCCCAAACTCTGGCTTTATAGCACATCCAT CCTGGCTTCTGGAGTCCCTACTCGCTTCAGTGGCAGTGGATCTGGGACCTCTTACT CTCTCACAATCAGCCGAATGGAGGCTGAAGATGCTGCCACTTATTACTGCCAGCA AAGGAGTAGTTCCCCATTCACGTTCGGCTCGGGGACAAAGCTCGAGATCAAACG AACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAA TCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCA AAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTG TCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGC TGAGCAAAGCAGACTACGAGAAACACAAAGTCTATGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTGCTAGTA TCGAGCGTCTGTCTTCTGGTCTGCGTATCAACAGCGCGAAAGACGATGCGGCAGG TCAGGCGATTGCTAACCGTTTTACCGCGAACATCAAAGGTCTGACTCAGGCTTCC CGTAACGCTAACGACGGTATCTCCATCGCGCAGACCACTGAAGGCGCGCTGAAC GAAATCAACAACAACCTGCAGCGTGTGCGTGAACTGGCGGTTCAGTCTGCTAAC AGCACTAACTCCC AGTCTGACCTCGACTCC ATCCAGGCTGAAATCACCC AGCGCC TGAACGAAATCGACCGTGTATCCGGTCAGACTCAGTTCAACGGCGTGAAAGTCCT GGCGCAGGACAACACCCTGACCATCCAGGTTGGTGCCAACGACGGTGAAACTAT CGATATCGATCTGAAGCAGATCAACTCTCAGACCCTGGGCCTGGATTCACTGAAC GTGCAGGCTAGTCAACCAGAGCTGGCGGAAGCAGCCGCTAAAACCACCGAAAAC CCGCTGCAGAAAATTGATGCCGCGCTGGCGCAGGTGGATGCGCTGCGCTCTGATC TGGGTGCGGTACAAAACCGTTTCAACTCCGCTATCACCAACTTGGGCAATACCGT AAACAACCTGTCTGAAGCGCGTAGCCGTATCGAAGATTCCGACTACGCGACCGA AGTTTCCAACATGTCTCGCGCGCAGATTCTGCAGGCTAGCTGA(SEQ ID NO :62) [manti-CD40_12E12.3F3_K-LV-hIgGK-C-Flgn-l-Flgn-2] [Flgn-l-Flgn-2 is shown in double underline]

DIQMTQTTSSLSASLGDRVTISCSASQGISNYLNWYQQKPDGTVKLLIYYTSILHSGVP SRFSGSGSGTDYSLTIGNLEPEDIATYYCQQFNKLPPTFGGGTKLEIKRTVAAPSVFIFP PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL SSTLTLSKADYEKHKVYACEVTHOGLSSPVTKSFNRGECASIERLSSGLRI SAKDDA AGOAIANRFTANIKGLTOASRNANDGISIAOTTEGALNEINNNLORVRELAVOSANST NSOSDLDSIOAEITORLNEIDRVSGOTOFNGVKVLAODNTLTIOVGANDGETIDIDLK QINSOTLGLDSLNVOASOPELAEAAAKTTENPLOKIDAALAOVDALRSDLGAVONRF NSAITNLGNTVNNLSEARSRIEDSDYATEVSNMSRAOILOASiSEO ID NO :63)

[00196] This can be used to attach to the DC-targeting vaccine the immunostimulatory properties of flagellin, in this example, via direct fusion to the L chain component.

ATGTCCTCTGCTCAGTTCCTTGGTCTCCTGTTGCTCTGTTTTCAAGGTACCAGATG TGATATCCAGATGACACAGACTACATCCTCCCTGTCTGCCTCTCTAGGAGACAGA GTCACCATCAGTTGCAGTGCAAGTCAGGGCATTAGCAATTATTTAAACTGGTATC AGCAGAAACCAGATGGAACTGTTAAACTCCTGATCTATTACACATCAATTTTACA CTCAGGAGTCCCATCAAGGTTCAGTGGCAGTGGGTCTGGGACAGATTATTCTCTC ACCATCGGCAACCTGGAACCTGAAGATATTGCCACTTACTATTGTCAGCAGTTTA ATAAGCTTCCTCCGACGTTCGGTGGAGGCACCAAACTCGAGATCAAACGAACTG TGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGG AACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTA CAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACA GAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGC AAAGCAGACTACGAGAAACACAAAGTCTATGCCTGCGAAGTCACCCATCAGGGC CTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTGCTAGTATCGAG CGTCTGTCTTCTGGTCTGCGTATCAACAGCGCGAAAGACGATGCGGCAGGTCAGG CGATTGCTAACCGTTTTACCGCGAACATCAAAGGTCTGACTCAGGCTTCCCGTAA CGCTAACGACGGTATCTCCATCGCGCAGACCACTGAAGGCGCGCTGAACGAAAT CAACAACAACCTGCAGCGTGTGCGTGAACTGGCGGTTCAGTCTGCTAACAGCACT AACTCCCAGTCTGACCTCGACTCCATCCAGGCTGAAATCACCCAGCGCCTGAACG AAATCGACCGTGTATCCGGTCAGACTCAGTTCAACGGCGTGAAAGTCCTGGCGC AGGACAACACCCTGACCATCCAGGTTGGTGCCAACGACGGTGAAACTATCGATA TCGATCTGAAGCAGATCAACTCTCAGACCCTGGGCCTGGATTCACTGAACGTGCA GGCTAGTCAACCAGAGCTGGCGGAAGCAGCCGCTAAAACCACCGAAAACCCGCT GCAGAAAATTGATGCCGCGCTGGCGCAGGTGGATGCGCTGCGCTCTGATCTGGG TGCGGTACAAAACCGTTTCAACTCCGCTATCACCAACTTGGGCAATACCGTAAAC AACCTGTCTGAAGCGCGTAGCCGTATCGAAGATTCCGACTACGCGACCGAAGTTT CCAACATGTCTCGCGCGCAGATTCTGCAGGCTAGCTGA(SEQ ID NO :64)

[SLAML-6xHis-Cohesin-Flgn-l-Flgn-2] [Flgn-l-Flgn-2 is shown in double underline; Cohesin is shown in single underline]

LDITSHHHHHHDDLDAVRI VDTVNAKPGDTVRIPVRFSGIPSKGIANCDFVYSYDPN VLEIIEIEPGDIIVDPNPDKSFDTAVYPDRKIIVFLFAEDSGTGAYAITKDGVFATIVAK V EGAPNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGDTTEPATPTTPVTTPTT TDDLDAASIERLSSGLRINSAKDDAAGOAIANRFTANIKGLTOASRNANDGISIAOTT EGALNEINNNLORVRELAVOSANSTNSOSDLDSIOAEITORLNEIDRVSGOTOFNGVK VLAODNTLTIOVGANDGETIDIDLKOINSOTLGLDSLNVOASOPELAEAAAKTTENPL OKIDAALAOVDALRSDLGAVONRFNSAITNLGNTVNNLSEARSRIEDSDYATEVSNM SRAOILOASiSEO ID NO :65) [00197] This can be used to attach to the DC-targeting vaccine the immunostimulatory properties of flagellin. ATGGATCCCAAAGGATCCCTTTCCTGGAGAATACTTCTGTTTCTCTCCCTGGCTTT TGAGTTGAGCTACGGACTCGACATCACATCCCACCATCACCATCACCATGACGAT CTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAGACACA GTAAGAATACCTGTAAGATTCAGCGGTATACCATCCAAGGGAATAGCAAACTGT GACTTTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAGAACCG GGAGACATAATAGTTGACCCGAATCCTGACAAGAGCTTTGATACTGCAGTATATC CTGACAGAAAGATAATAGTATTCCTGTTTGCAGAAGACAGCGGAACAGGAGCGT ATGCAATAACTAAAGACGGAGTATTTGCTACGATAGTAGCGAAAGTAAAAGAAG GAGCACCTAACGGACTCAGTGTAATCAAATTTGTAGAAGTAGGCGGATTTGCGA ACAATGACCTTGTAGAACAGAAGAC ACAGTTCTTTGACGGTGGAGTAAATGTTG GAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAA CAGATGATCTGGATGCAGCTAGTATCGAGCGTCTGTCTTCTGGTCTGCGTATCAA CAGCGCGAAAGACGATGCGGCAGGTCAGGCGATTGCTAACCGTTTTACCGCGAA CATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGTATCTCCATCGCG CAGACCACTGAAGGCGCGCTGAACGAAATCAACAACAACCTGCAGCGTGTGCGT GAACTGGCGGTTCAGTCTGCTAACAGCACTAACTCCCAGTCTGACCTCGACTCCA TCCAGGCTGAAATCACCCAGCGCCTGAACGAAATCGACCGTGTATCCGGTCAGA CTCAGTTCAACGGCGTGAAAGTCCTGGCGCAGGACAACACCCTGACCATCCAGG TTGGTGCCAACGACGGTGAAACTATCGATATCGATCTGAAGCAGATCAACTCTCA GACCCTGGGCCTGGATTCACTGAACGTGCAGGCTAGTCAACCAGAGCTGGCGGA AGCAGCCGCTAAAACCACCGAAAACCCGCTGCAGAAAATTGATGCCGCGCTGGC GCAGGTGGATGCGCTGCGCTCTGATCTGGGTGCGGTACAAAACCGTTTCAACTCC GCTATCACCAACTTGGGCAATACCGTAAACAACCTGTCTGAAGCGCGTAGCCGTA TCGAAGATTCCGACTACGCGACCGAAGTTTCCAACATGTCTCGCGCGCAGATTCT GCAGGCTAGCTGA(SEQ ID NO :66)

[SLAML-Cohesin-hIL-21] [hlL-21 is shown in double underline; Cohesin is shown in single underline]

LDDLDAVRIKVDTVNA PGDTVRIPVRFSGIPSKGIANCDFVYSYDPNVLEIIEIEPGDI IVDPNPDKSFDTAVYPDRKIIVFLFAEDSGTGAYAITKDGVFATIVAKVKEGAPNGLS VIKFVEVGGFAN DLVEQKTQFFDGGVNVGDTTEPATPTTPVTTPTTTDDLDALEAD OGODRHMIRMROLIDIVDOLKNYVNDLVPEFLPAPEDVETNCEWSAFSCFOKAOLK SANTGNNERIINVSIKKLKRKPPSTNAGRROKHRLTCPSCDSYEK PPKEFLERFKSLL OKMIHOHLSSRTHGSEDSfSEO ID NO :67)

[00198] This can be used to attach to the DC-targeting vaccine the immunostimulatory properties of interleukin-21.

ATGGATCCCAAAGGATCCCTTTCCTGGAGAATACTTCTGTTTCTCTCCCTGGCTTT TGAGTTGAGCTACGGACTCGACGATCTGGATGCAGTAAGGATTAAAGTGGACAC AGTAAATGCAAAACCGGGAGACACAGTAAGAATACCTGTAAGATTCAGCGGTAT ACCATCCAAGGGAATAGCAAACTGTGACTTTGTATACAGCTATGACCCGAATGTA CTTGAGATAATAGAGATAGAACCGGGAGACATAATAGTTGACCCGAATCCTGAC AAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATAATAGTATTCCTGTTTG CAGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGACTCAGTGTAATCAAAT TTGTAGAAGTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGT TCTTTGACGGTGGAGTAAATGTTGGAGATACAACAGAACCTGCAACACCTACAA CACCTGTAACAACACCGACAACAACAGATGATCTGGATGCACTCGAGGCTGACC AAGGTCAAGATCGCCACATGATTAGAATGCGTCAACTTATAGATATTGTTGATCA GCTGAAAAATTATGTGAATGACTTGGTCCCTGAATTTCTGCCAGCTCCAGAAGAT GTAGAGACAAACTGTGAGTGGTCAGCTTTTTCCTGYTTTCAGAAGGCCCAACTAA AGTCAGCAAATACAGGAAACAATGAAAGGATAATCAATGTATCAATTAAAAAGC TGAAGAGGAAACCACCTTCCACAAATGCAGGGAGAAGACAGAAACACAGACTA ACATGCCCTTCATGTGATTCTTATGAGAAAAAACCACCCAAAGAATTCCTAGAAA GATTCAAATCACTTCTCCAAAAGATGATTCATCAGCATCTGTCCTCTAGAACACA CGGAAGTGAAGATTCCTGA(SEQ ID NO :68) [SLAML-Cohesin-hIL-2-vl] [hIL-2-vl is shown in double underline; Cohesin is shown in single underline]

LDDLDAVRIKVDTVNAKPGDTVRIPVRFSGIPSKGIANCDFVYSYDPNVLEIIEIEPGDI IVDPNPDKSFDTAVYPDRKIIVFLFAEDSGTGAYAITKDGVFATIVAKVKEGAPNGLS VIKFVEVGGFAN DLVEQKTQFFDGGANVGDTTEPATPTTPVTTPTTTDDLDAASPS S S STKKTOLOLEHLLLDLOMILNGINN YKNPKLTSMLTFKF YMPKKATELKHLOCLE EELKPLEEVLNLAOSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLN RWITFCOSIISTLTiSEO ID NO :69)

[00199] These can be used to attach to the DC-targeting vaccine the immuno stimulatory properties of interleukin-2.

ATGGATCCCAAAGGATCCCTTTCCTGGAGAATACTTCTGTTTCTCTCCCTGGCTTT TGAGTTGAGCTACGGACTCGACGATCTGGATGCAGTAAGGATTAAAGTGGACAC AGTAAATGCAAAACCGGGAGACACAGTAAGAATACCTGTAAGATTCAGCGGTAT ACCATCCAAGGGAATAGCAAACTGTGACTTTGTATACAGCTATGACCCGAATGTA CTTGAGATAATAGAGATAGAACCGGGAGACATAATAGTTGACCCGAATCCTGAC AAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATAATAGTATTCCTGTTTG CAGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGACTCAGTGTAATCAAAT TTGTAGAAGTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGT TCTTTGACGGTGGAGCAAATGTTGGAGATAC AAC AGAACCTGC AACACCTACAA CACCTGTAACAACACCGACAACAACAGATGATCTGGATGCAGCTAGCCCCTCCA GCAGCAGCACCAAGAAGACCCAGCTGCAGCTGGAGCACCTGCTGCTGGACCTGC AGATGATCCTGAACGGCATCAACAACTACAAGAACCCCAAGCTGACCAGCATGC TGACGTTTAAATTTTACATGCCCAAGAAGGCCACAGAACTGAAACATCTTCAGTG TCT AGAAGAAG AACTC AAACCTCTGGAGGAAGTGCTAA ATTTAGCTC AAAGC AA AAACTTTCACTTAAGACCCAGGGACTTAATCAGCAATATCAACGTAATAGTTCTG GAACTAAAGGGATCTGAAACAACATTCATGTGTGAATATGCTGATGAGACAGCA ACCATTGTAGAATTTCTGAACAGATGGATTACCTTTTGTCAAAGCATCATCTCAA CACTGACTTGA(SEQ ID NO :70)

[SLAML-6xHis-Cohesin-hIL-2-vl] [hIL-2-vl is shown in double underline; Cohesin is shown in single underline]

LDITSHHHHHHDDLDAVRIKVDTVNAKPGDTVRIPVRFSGIPSKGIANCDFVYSYDPN VLEIIEIEPGDIIVDPNPDKSFDTAVYPDRKHVFLFAEDSGTGAYAITKDGVFATIVAK VKEGAPNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGDTTEPATPTTPVTTPTT TDDLDAASPSSS STKKTOLOLEHLLLDLOMILNGINN YKNPKLTSMLTFKF YMPKKA TELKHLOCLEEELKPLEEVLNLAOSKNFHLRPRDLISNINVIVLELKGSETTFMCEYA DETATIVEFLNRWITFCOSIISTLTiSEO ID NO :71) ATGGATCCCAAAGGATCCCTTTCCTGGAGAATACTTCTGTTTCTCTCCCTGGCTTT TGAGTTGAGCTACGGACTCGACATCACATCCCACCATCACCATCACCATGACGAT CTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAGACACA GTAAGAATACCTGTAAGATTCAGCGGTATACCATCCAAGGGAATAGCAAACTGT GACTTTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAGAACCG GGAGACATAATAGTTGACCCGAATCCTGACAAGAGCTTTGATACTGCAGTATATC CTGACAGAAAGATAATAGTATTCCTGTTTGCAGAAGACAGCGGAACAGGAGCGT ATGCAATAACTAAAGACGGAGTATTTGCTACGATAGTAGCGAAAGTAAAAGAAG GAGCACCTAACGGACTCAGTGTAATCAAATTTGTAGAAGTAGGCGGATTTGCGA ACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTAAATGTTG GAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAA CAGATGATCTGGATGCAGCTAGCCCCTCCAGCAGCAGCACCAAGAAGACCCAGC TGCAGCTGGAGCACCTGCTGCTGGACCTGCAGATGATCCTGAACGGCATCAACA ACTACAAGAACCCCAAGCTGACCAGCATGCTGACGTTTAAATTTTACATGCCCAA GAAGGCCACAGAACTGAAACATCTTCAGTGTCTAGAAGAAGAACTCAAACCTCT GGAGGAAGTGCTAAATTTAGCTCAAAGCAAAAACTTTCACTTAAGACCCAGGGA CTTAATCAGCAATATCAACGTAATAGTTCTGGAACTAAAGGGATCTGAAACAAC ATTCATGTGTGAATATGCTGATGAGACAGCAACCATTGTAGAATTTCTGAACAGA TGGATTACCTTTTGTCAAAGCATCATCTCAACACTGACTTGA(SEQ ID NO :72)

[SLAML-6xHis-Cohesin-hIL-9] [hIL-9 is shown in double underline; Cohesin is shown in single underline]

LDITSHHHHHHDDLDAVRIKVDTVNAKPGDTVRIPVRFSGIPSKGIANCDFVYSYDPN VLEIIEIEPGDIIVDPNPDKSFDTAVYPDRKIIVFLFAEDSGTGAYAITKDGVFATIVA VKEGAPNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGDTTEPATPTTPVTTPTT TDDLDAASOGCPTLAGILDINFLINKMOEDPASKCHCSANVTSCLCLGIPSDNCTRPC FSERLSOMTNTTMOTRYPLIFSRVKKSVEVLKNNKCPYFSCEOPCNOTTAGNALTFL KSLLEIFOKEKMRGMRGKIfSEO ID NO :73)

[00200] This can be used to attach to the DC-targeting vaccine the immunostimulatory properties of interleukin-9.

ATGGATCCCAAAGGATCCCTTTCCTGGAGAATACTTCTGTTTCTCTCCCTGGCTTT TGAGTTGAGCTACGGACTCGACATCACATCCCACCATCACCATCACCATGACGAT CTGGATGCAGTAAGGATTAAAGTGGAC ACAGTAAATGC AAAACCGGGAGAC AC A GTAAGAATACCTGTAAGATTCAGCGGTATACCATCCAAGGGAATAGCAAACTGT GACTTTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAGAACCG GGAGACATAATAGTTGACCCGAATCCTGACAAGAGCTTTGATACTGCAGTATATC CTGACAGAAAGATAATAGTATTCCTGTTTGCAGAAGACAGCGGAACAGGAGCGT ATGCAATAACTAAAGACGGAGTATTTGCTACGATAGTAGCGAAAGTAAAAGAAG GAGCACCTAACGGACTCAGTGTAATCAAATTTGTAGAAGTAGGCGGATTTGCGA ACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTAAATGTTG GAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAA CAGATGATCTGGATGCAGCTAGCCAGGGGTGTCCAACCTTGGCGGGGATCCTGG ACATCAACTTCCTCATCAACAAGATGCAGGAAGATCCAGCTTCCAAGTGCCACTG CAGTGCTAATGTGACCAGTTGTCTCTGTTTGGGCATTCCCTCTGACAACTGCACC AGACCATGCTTCAGTGAGAGACTGTCTCAGATGACCAATACCACCATGCAAACA AGATACCCACTGATTTTCAGTCGGGTGAAAAAATCAGTTGAAGTACTAAAGAAC AACAAGTGTCCATATTTTTCCTGTGAACAGCCATGCAACCAAACCACGGCAGGCA ACGCGCTGACATTTCTGAAGAGTCTTCTGGAAATTTTCCAGAAAGAAAAGATGA GAGGGATGAGAGGCAAGATATGA(SEQ ID NO :74)

[SLAML-6xHis-Cohesin-FIuHAb-l] [FluHAb-1 is shown in double underline; Cohesin is shown in single underline]

DITSHHHHHHDDLDAVRIKVDTVNAKPGDTVRIPVRFSGIPSKGIANCDFVYSYDPNV LEIIEIEPGDIIVDPNPDKSFDTAVYPDR IIVFLFAEDSGTGAYAITKDGVFATIVAKV KEGAPNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGDTTEPATPTTPVTTPTTT DDLDAASDRICTGITSSNSPHVVKTATOGEVNVTGVIPLTTTPTKSHFANLKGTETRG KLCPKCLNCTDLDVALGRPKCTGKIPSARVSILHEVRPVTSGCFPIMHDRTKIROLPN LLRGYEHIRLSTHNVINAENAPGGPYKIGTSGSCPNITNGNGFFATMAWAVPKNDKN KTATNPLTIEVPYICTEGEDOITVWGFHSDDETOMAKLYGDSKPOKFTSSANGVTTH YVSOIGGFPNOTEDGGLPOSGRIVVDYMVOKSGKTGTITYORGILLPOKVWCASGRS KVIKGSLPLIGEADCLHEKYGGLN SKPYYTGEHAKAIGNCPIWVKTPL LANGT CS EQ ID NO :75)

[00201] This shows a Influenza B strain HA1 domain which can be a antigen component of Dc-targeting vaccines, in this example linked though a dockerin domain fused to the DC-targeting antibody complex.

ATGGATCCCAAAGGATCCCTTTCCTGGAGAATACTTCTGTTTCTCTCCCTGGCTTT TGAGTTGAGCTACGGACTCGACATCACATCCCACCATCACCATCACCATGACGAT CTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAGACACA GTAAGAATACCTGTAAGATTCAGCGGTATACCATCCAAGGGAATAGCAAACTGT GACTTTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAGAACCG GGAGACATAATAGTTGACCCGAATCCTGACAAGAGCTTTGATACTGCAGTATATC CTGACAGAAAGATAATAGTATTCCTGTTTGCAGAAGACAGCGGAACAGGAGCGT ATGCAATAACTAAAGACGGAGTATTTGCTACGATAGTAGCGAAAGTAAAAGAAG GAGCACCTAACGGACTCAGTGTAATCAAATTTGTAGAAGTAGGCGGATTTGCGA ACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTAAATGTTG GAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAA CAGATGATCTGGATGCAGCTAGCGATCGAATCTGCACTGGAATAACATCGTCAA ACTCACCACATGTCGTCAAAACTGCTACTCAAGGGGAGGTCAATGTGACAGGTG TAATACCACTGACAACAACACCCACCAAATCTCATTTTGCAAATCTCAAAGGAAC AGAAACCAGGGGGAAACTATGCCCAAAATGCCTCAACTGCACAGATCTGGACGT AGCCTTGGGCAGACCAAAATGCACGGGGAAAATACCCTCGGCAAGAGTTTCAAT ACTCCATGAAGTCAGACCTGTTACATCTGGGTGCTTTCCTATAATGCACGACAGA ACAAAAATTAGACAGCTGCCTAACCTTCTCCGAGGATACGAACATATCAGGTTAT CAACCCATAACGTTATCAATGCAGAAAATGCACCAGGAGGACCCTACAAAATTG GAACCTCAGGGTCTTGCCCTAACATTACCAATGGAAACGGATTTTTCGCAACAAT GGCTTGGGCCGTCCCAAAAAACGACAAAAACAAAACAGCAACAAATCCATTAAC AATAGAAGTACCATACATTTGTACAGAAGGAGAAGACCAAATTACCGTTTGGGG GTTCCACTCTGACGACGAGACCCAAATGGCAAAGCTCTATGGGGACTCAAAGCC CCAGAAGTTCACCTCATCTGCCAACGGAGTGACCACACATTACGTTTCACAGATT GGTGGCTTCCCAAATCAAACAGAAGACGGAGGACTACCACAAAGTGGTAGAATT GTTGTTGATTACATGGTGCAAAAATCTGGGAAAACAGGAACAATTACCTATCAA AGGGGTATTTTATTGCCTCAAAAGGTGTGGTGCGCAAGTGGCAGGAGCAAGGTA ATAAAAGGATCCTTGCCTTTAATTGGAGAAGCAGATTGCCTCCACGAAAAATAC GGTGGATTAAACAAAAGCAAGCCTTACTACACAGGGGAACATGCAAAGGCCATA GGAAATTGCCCAATATGGGTGAAAACACCCTTGAAGCTGGCCAATGGAACCAAA TGA(SEQ ID NO :76)

[SLAML-6xHis-Cohesin-hIFN.A7-2] [MFN.A7-2 is shown in double underline; Cohesin is shown in single underline]

DITSHHHHHHDDLDAVRIKVDTVNAKPGDTVRIPVRFSGIPSKGIANCDFVYSYDPNV LEIIEIEPGDIIVDPNPDKSFDTAVYPDRKIIVFLFAEDSGTGAYAITKDGVFATIVAKV EGAPNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGDTTEPATPTTPVTTPTTT DDLDAASCDLPOTHSLRNRRALILLAOMGRISPFSCLKDRHEFRFPEEEFDGHOFOKT OAISVLHEMIOOTFNLFSTEDSSAAWEOSLLEKFSTELYOOLNDLEACVIOEVGVEET PLMNEDFILAVRKYFQRITLYLMEKKYSPCAWEVVRAEIMRSFSFSTNLKKGLRRKD

(SEQ ID NO :77)

[00202] This can be used to attach to the DC-targeting vaccine the immunostimulatory properties of interferon alpha.

ATGGATCCCAAAGGATCCCTTTCCTGGAGAATACTTCTGTTTCTCTCCCTGGCTTT TGAGTTGAGCTACGGACTCGACATCACATCCCACCATCACCATCACCATGACGAT CTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAGACACA GTAAGAATACCTGTAAGATTCAGCGGTATACCATCCAAGGGAATAGCAAACTGT GACTTTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAGAACCG GGAGACATAATAGTTGACCCGAATCCTGACAAGAGCTTTGATACTGCAGTATATC CTGACAGAAAGATAATAGTATTCCTGTTTGCAGAAGACAGCGGAACAGGAGCGT ATGCAATAACTAAAGACGGAGTATTTGCTACGATAGTAGCGAAAGTAAAAGAAG GAGCACCTAACGGACTCAGTGTAATCAAATTTGTAGAAGTAGGCGGATTTGCGA ACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTAAATGTTG GAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAA CAGATGATCTGGATGCAGCTAGCTGTGATCTGCCTCAGACCCACAGCCTGCGTAA TAGGAGGGCCTTGATACTCCTGGC AC AAATGGGAAGAATCTCTCCTTTCTCCTGC TTGAAGGACAGACATGAATTCAGATTCCCAGAGGAGGAGTTTGATGGCCACCAG TTCCAGAAGACTCAAGCCATCTCTGTCCTCCATGAGATGATCCAGCAGACCTTCA ATCTCTTCAGCACAGAGGACTCATCTGCTGCTTGGGAACAGAGCCTCCTAGAAAA ATTTTCCACTGAACTTTACCAGCAACTGAATGACCTGGAAGCATGTGTGATACAG GAGGTTGGGGTGGAAGAGACTCCCCTGATGAATGAGGACTTCATCCTGGCTGTG AGGAAATACTTCCAAAGAATCACTCTTTATCTAATGGAGAAGAAATACAGCCCTT GTGCCTGGGAGGTTGTCAGAGCAGAAATCATGAGATCCTTCTCTTTTTCAACAAA CTTGAAAAAAGGATTAAGGAGGAAGGATTGA(SEQ ID NO :78) [SLAML-6xHis-Cohesin-hIL-10] [hIL-10 is shown in double underline; Cohesin is shown in single underline]

DITSHHHHHHDDLDAVRI VDTVNAKPGDTVRIPVRFSGIPSKGIANCDFVYSYDPNV LEIIEIEPGDIIVDPNPDKSFDTAVYPDRKIIVFLFAEDSGTGAYAITKDGVFATIVAKV KEGAPNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGDTTEPATPTTPVTTPTTT DDLDAASPGOGTOSENSCTHFPGNLPNMLRDLRDAFSRVKTFFOMKDOLDNLLLKE SLLEDFKGYLGCOALSEMIOFYLEEVMPOAENODPDIKAHVNSLGENLKTLRLRLRR CHRFLPCENKSKAVEOVKNAFNKLOEKGIYKAMSEFDIFINYIEAYMTMKIRNiSEO ID NO :79) [00203] This can be used to attach to the DC-targeting vaccine the immuno stimulatory properties of interleukin-10.

ATGGATCCCAAAGGATCCCTTTCCTGGAGAATACTTCTGTTTCTCTCCCTGGCTTT TGAGTTGAGCTACGGACTCGACATCACATCCCACCATCACCATCACCATGACGAT CTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAGACACA GTAAGAATACCTGTAAGATTCAGCGGTATACCATCCAAGGGAATAGCAAACTGT GACTTTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAGAACCG GGAGACATAATAGTTGACCCGAATCCTGACAAGAGCTTTGATACTGCAGTATATC CTGACAGAAAGATAATAGTATTCCTGTTTGCAGAAGACAGCGGAAC AGGAGCGT ATGCAATAACTAAAGACGGAGTATTTGCTACGATAGTAGCGAAAGTAAAAGAAG GAGCACCTAACGGACTCAGTGTAATCAAATTTGTAGAAGTAGGCGGATTTGCGA ACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTAAATGTTG GAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAA CAGATGATCTGGATGCAGCTAGCCCAGGCCAGGGCACCCAGTCTGAGAACAGCT GCACCCACTTCCCAGGCAACCTGCCTAACATGCTTCGAGATCTCCGAGATGCCTT CAGCAGAGTGAAGACTTTCTTTCAAATGAAGGATCAGCTGGACAACTTGTTGTTA AAGGAGTCCTTGCTGGAGGACTTTAAGGGTTACCTGGGTTGCCAAGCCTTGTCTG AGATGATCCAGTTTTACCTGGAGGAGGTGATGCCCCAAGCTGAGAACCAAGACC CAGACATCAAGGCGCATGTGAACTCCCTGGGGGAGAACCTGAAGACCCTCAGGC TGAGGCTACGGCGCTGTCATCGATTTCTTCCCTGTGAAAACAAGAGCAAGGCCGT GGAGCAGGTGAAGAATGCCTTTAATAAGCTCCAAGAGAAAGGCATCTACAAAGC CATGAGTGAGTTTGACATCTTCATCAACTACATAGAAGCCTACATGACAATGAAG AT AC G A A ACTG A( SEQ ID NO :80)

[mAnti-LOX-115C4H-LV-hIgG4H-C-Flex-vl-FluM2e-ls] [FluM2e-l s is shown in double underline; Flex-vl is shown in single underline]

EIQLQQTGPETVKPGASVKISCKASGYPFTDYIMVWVKQSHGKSLEWIGNISPYYGTT NYNLKF GKATLTVDKSSSTAYMQLNSLTSEDSAVYYCARSPNWDGAWFAHWGQ GALVTVSAAKTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDH PSNTKVDKRVESKYGPPC PPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQ SLSLSLG ASQTPTN TISVTPTNNSTPTN SNPKPNPASLLTEVETPTRSEWECRCSDSSDPASrSEO ID NO :81)

[00204] The M2e module shown in grey is from the relatively conserved ectodomain of the M2 protein ectodomain from swine flu, and can be used directly fused to antibody or attached via cohesin-dockerin interaction to broaden protective antigenic responses of DC-targeting vaccines to include M2 epitopes.

ATGGGAGGGATCTGGATCTTTCTCTTCCTCCTGTCAGGAACTGCAGGTGCCCACT CTGAGATCCAGCTGCAGCAGACTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAG TGAAGATATCCTGCAAGGCTTCTGGTTATCCATTCACTGACTACATCATGGTCTG GGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGAAATATTAGTCCTTA CTATGGTACTACTAACTACAATCTGAAGTTCAAGGGCAAGGCCACATTGACTGTA GACAAATCTTCCAGCACAGCCTACATGCAGCTCAACAGTCTGACATCTGAGGACT CTGCAGTCTATTACTGTGCAAGATCCCCTAACTGGGACGGGGCCTGGTTTGCTCA CTGGGGCCAAGGGGCTCTGGTCACTGTCTCTGCAGCCAAAACAAAGGGCCCATC CGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTG GGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAG GCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACT CTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACC TACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGG ACAAGAGAGTT GAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGGGG GACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCG GACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGT CCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCC GCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCT GCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGG CCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA GCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGT CAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGG GAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGC AGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTA CACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGTCAGACCCCCACCAAC ACCATCAGCGTGACCCCCACCAACAACAGCACCCCCACCAACAACAGCAACCCC AAGCCCAACCCCGCTAGTCTGCTGACCGAGGTGGAGACCCCCACCCGGAGCGAG TGGGAGTGCCGGTGCAGCGACAGCAGCGACCCCGCTAGCTGA(SEQ ID NO :82)

[mAnti-LOX-115C4H-LV-hIgG4H-C-Flex-vl-FluM2e-ls-FluM2-l] [FluM2e-l s and FluM2-l are shown in double underline; Flex-vl is shown in single underline]

EIQLQQTGPELVKPGASVKISCKASGYPFTDYIMVWVKQSHGKSLEWIGNISPYYGT T NYNLKFKGKATLTVDKSSSTAYMQLNSLTSEDSAVYYCARSPNWDGAWFAHWGQ GALVTVSAAKTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNT VDKRVESKYGPPC PPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKASQTPTN TISVTPTNNSTPTNNSNP PNPASLLTEVETPTRSEWECRCSDSSDPASLLTEVETPIRN EWGCRCNGSSDPASiSEO ID NO :83)

[00205] The M2e modules shown in grey are from relatively conserved ectodomain of the M2 protein ectodomain, and can be used directly fused to antibody or attached via cohesin-dockerin interaction to broaden protective antigenic responses of DC- targeting vaccines to include M2 epitopes. ATGGGAGGGATCTGGATCTTTCTCTTCCTCCTGTCAGGAACTGCAGGTGCCCACT CTGAGATCCAGCTGCAGCAGACTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAG TGAAGATATCCTGCAAGGCTTCTGGTTATCCATTCACTGACTACATCATGGTCTG GGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGAAATATTAGTCCTTA CTATGGTACTACTAACTACAATCTGAAGTTCAAGGGCAAGGCCACATTGACTGTA GACAAATCTTCCAGCACAGCCTACATGCAGCTCAACAGTCTGACATCTGAGGACT CTGCAGTCTATTACTGTGCAAGATCCCCTAACTGGGACGGGGCCTGGTTTGCTCA CTGGGGCCAAGGGGCTCTGGTCACTGTCTCTGCAGCCAAAACAAAGGGCCCATC CGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTG GGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAG GCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACT CTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACC TACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTT GAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGGGG GACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCG GACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGT CCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCC GCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCT GCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGG CCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA GCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGT CAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGG GAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGC AGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTA CACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGTCAGACCCCCACCAAC ACCATCAGCGTGACCCCCACCAACAACAGCACCCCCACCAACAACAGCAACCCC AAGCCCAACCCCGCTAGTCTGCTGACCGAGGTGGAGACCCCCACCCGGAGCGAG TGGGAGTGCCGGTGCAGCGACAGCAGCGACCCCGCTAGTCTGCTGACAGAGGTG GAGACCCCTATCCGGAATGAATGGGGATGCCGGTGTAACGGCAGCAGCGACCCC GCTAGCTGA(SEQ ID NO :84) [Ecoli-pET28[6xHis-Cohesin-PE38-vl] [PE38-vl is shown in double underline; Cohesin is shown in single underline]

MGSSHHHHHHSSGLVPRGSHMASMDLDAVRIKVDTVNAKPGDTVNIPVRFSGIPSK GIANCDFVYSYDPNVLEIIEIKPGELIVDPNPTKSFDTAVYPDRKMIVFLFAEDSGTGA YAITKDGVFATIVAKV EGAPNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGD TTEPATPTTPVTTPTTTDDLDAASEGGSLAALTAHOACHLPLETFTRHROPRGWEOL EOCGYPVORLVALYLAARLSWNOVDOVIRNALASPGSGGDLGEAIREOPEQARLAL TLAAAESERFVROGTGNDEAGAANGPADSGDALLERNYPTGAEFLGDGGDVSFSTR GTONWTVERLLOAHROLEERGYVFVGYHGTFLEAAOSIVFGGVRARSODLDAIWRG FYIAGDPALAYGYAODOEPDARGRIRNGALLRVYVPRSSLPGFYRTSLTLAAPEAAG EVERLIGHPLPLRLDAITGPEEEGGRLETILGWPLAERTVVIPSAIPTDPRNVGGDLDPS SIPDKEOAISALPDYASOPGKPPKDELfSEO ID NO :85)

[00206] This permits attachment to the vaccine of a toxin, which will deliver a death signal to cells also receiving antigen, thereby augmenting vaccine efficacy. ATGGGCAGCAGCCATCATCATCATCATCACAGCAGCGGCCTGGTGCCGCGCGGC AGCCATATGGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTA AATGCAAAACCGGGAGACACAGTAAATATACCTGTAAGATTCAGTGGTATACCA TCCAAGGGAATAGCAAACTGTGACTTTGTATACAGCTATGACCCGAATGTACTTG AGATAATAGAGATAAAACCGGGAGAATTGATAGTTGACCCGAATCCTACCAAGA GCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTATTCCTGTTTGCGGA AGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTACGAT AGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGT AGAAGTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTT TGACGGTGGAGTAAATGTTGGAGATACAACAGAACCTGCAACACCTACAACACC TGTAACAACACCGACAACAACAGATGATCTAGATGCAGCTAGCGAGGGCGGCAG CCTGGCCGCGCTGACCGCGCACCAGGCTTGCCACCTGCCGCTGGAGACTTTCACC CGTCATCGCCAGCCGCGCGGCTGGGAACAACTGGAGCAGTGCGGCTATCCGGTG CAGCGGCTGGTCGCCCTCTACCTGGCGGCGCGGCTGTCGTGGAACCAGGTCGACC AGGTGATCCGCAACGCCCTGGCCAGCCCCGGCAGCGGCGGCGACCTGGGCGAAG CGATCCGCGAGCAGCCGGAGCAAGCCCGTCTGGCCCTGACCCTGGCCGCCGCCG AGAGCGAGCGCTTCGTCCGGCAGGGCACCGGCAACGACGAGGCCGGCGCGGCCA ACGGCCCGGCGGACAGCGGCGACGCCCTGCTGGAGCGCAACTATCCCACTGGCG CGGAGTTCCTCGGCGACGGCGGCGACGTCAGCTTCAGCACCCGCGGCACGCAGA ACTGGACGGTGGAGCGGCTGCTCCAGGCGCACCGCCAACTGGAGGAGCGCGGCT ATGTGTTCGTCGGCTACCACGGCACCTTCCTCGAAGCGGCGCAAAGCATCGTCTT CGGCGGGGTGCGCGCGCGCAGCCAGGACCTCGACGCGATCTGGCGCGGTTTCTA TATCGCCGGCGATCCGGCGCTGGCCTACGGCTACGCCCAGGACCAGGAACCCGA CGCACGCGGCAGGATCCGCAACGGTGCCCTGCTGCGGGTCTATGTGCCGCGCTCG AGCCTGCCGGGCTTCTACCGCACCAGCCTGACCCTGGCCGCGCCGGAGGCGGCG GGCGAGGTCGAACGGCTGATCGGCCATCCGCTGCCGCTGCGCCTGGACGCCATC ACCGGCCCCGAGGAGGAAGGCGGGCGCCTGGAGACCATTCTCGGCTGGCCGCTG GCCGAGCGCACCGTGGTGATTCCCTCGGCGATCCCCACCGACCCGCGCAACGTCG GCGGCGACCTCGACCCGTCCAGCATCCCCGACAAGGAACAGGCGATCAGCGCCC TGCCGGACTACGCCAGCCAGCCCGGCAAACCGCCGAAGGACGAGCTGTAA(SEQ ID NO :86)

[Mam-cetHS-puro[SLAML-6xHis-Cohesin-hHLA-G] [hHLA-G is shown in double underline; Cohesin is shown in single underline]

LDITSHHHHHHDDLDAVRIKVDTVNA PGDTVRIPVRFSGIPSKGIANCDFVYSYDPN VLEIIEIEPGDIIVDPNPDKSFDTAVYPDRKIIVFLFAEDSGTGAYAITKDGVFATIVAK VKEGAPNGLSVIKFVEVGGFANNDLVEOKTQFFDGGVNVGDTTEPATPTTPVTTPTT TDDLDAASOATTAYFLYOOOGRLDKLTVTSONLOLENLRMKLPKPPKPVSKMRMA TPLLMOALPMGALPOGPMONAT YGNMTEDHVMHLLONADPLKVYPPLKGSFPEN LRHLKNTMETIDWKVFESWMHHWLLFEMSRHSLEOKPTDAPPKVLTKCOEEVSHIP AVHPGSFRPKCDENGNYLPLOCYGSIGYCWCVFPNGTEVPNTRSRGHHNCSESLELE DPSSGLGVTKODLGPVPMiSEO ID NO :87) [00207] This permits attachment to the vaccine of the HLA-DR antigens- associated invariant chain, which will augment antigen processing.

ATGGATCCCAAAGGATCCCTTTCCTGGAGAATACTTCTGTTTCTCTCCCTGGCTTT TGAGTTGAGCTACGGACTCGACATCACATCCCACCATCACCATCACCATGACGAT CTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAGACACA GTAAGAATACCTGTAAGATTCAGCGGTATACCATCCAAGGGAATAGCAAACTGT GACTTTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAGAACCG GGAGACATAATAGTTGACCCGAATCCTGACAAGAGCTTTGATACTGCAGTATATC CTGACAGAAAGATAATAGTATTCCTGTTTGCAGAAGACAGCGGAACAGGAGCGT ATGCAATAACTAAAGACGGAGTATTTGCTACGATAGTAGCGAAAGTAAAAGAAG GAGCACCTAACGGACTCAGTGTAATCAAATTTGTAGAAGTAGGCGGATTTGCGA ACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTAAATGTTG GAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAA CAGATGATCTGGATGCAGCTAGCCAGGCCACAACAGCCTACTTTCTCTACCAGCA GCAGGGAAGGCTCGACAAGCTCACTGTGACTTCCCAGAACCTCCAACTGGAGAA CCTGCGGATGAAACTGCCCAAACCCCCCAAGCCCGTCAGTAAGATGAGGATGGC AACACCCCTGCTGATGCAGGCTCTGCCAATGGGCGCCCTGCCCCAGGGGCCTATG CAGAATGCTACCAAGTATGGGAACATGACCGAGGACCACGTCATGCACCTCCTG CAGAACGCCGATCC ACTCAAGGTGTACCCACC ACTGAAGGGGTCCTTTCCCGAG AACCTTCGGCACTTGAAGAACACCATGGAGACCATCGACTGGAAAGTGTTCGAG AGCTGGATGCACCATTGGTTGCTCTTCGAGATGTCCCGGCACTCACTGGAGCAGA AGCCTACAGACGCCCCACCCAAGGTGTTGACAAAGTGCCAGGAAGAGGTGTCTC ACATCCCAGCCGTGCATCCCGGCAGCTTTCGCCCCAAGTGCGATGAGAACGGGA ACTACCTTCCTCTGCAGTGCTACGGGAGCATTGGCTACTGCTGGTGTGTGTTCCCT AACGGCACTGAGGTCCCAAACACAAGAAGCAGGGGACACCATAACTGTAGCGA GTCCTTGGAACTGGAAGATCCTTCCAGCGGGCTGGGCGTCACCAAGCAGGATCT GGGCCCTGTGCCCATGTGA(SEQ ID NO :88) [manti-CD40_12E12.3F3_H-LV-hIgG4H-C-Flex-vl-FluM2-5-Pep-l-vl -Pep-3-B] [

FluM2-5-Pep-l-vl-Pep-3 is shown in double underline; Flex-vl and O are shown in single underline.

EVKLVESGGGLVQPGGSLKLSCATSGFTFSDYYMYWVRQTPEKRLEWVAYINSGGG STYYPDTVKGRFTISRDNAKNTLYLQMSRLKSEDTAMYYCARRGLPFHAMDYWGQ GTSVTVSSA TKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPP CPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVH NAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQ PREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWOEGNVFSCSVMHEALHNHYTQKSLSLSLGKASQTPTNTI SVTPTNNSTPTNNSNPKPNPASLLTEVETPIRNEWECRCSDSSDPIVVAANIIASAGVP ESMREEYROEOOSAVDVDDGHFVNIELEASTVTPTATATPSAIVTTITPTATTKPASCS EQ ID NO :89) [00208] This shows a configuration of M2 epitopes in grey that are expressible directly linked to antibody or to cohesin. They can be used as a antigen module to broaden protective immunity by adding relatively well conserved M2 epitopes.

ATGAACTTGGGGCTCAGCTTGATTTTCCTTGTCCTTGTTTTAAAAGGTGTCCAGTG TGAAGTGAAGCTGGTGGAGTCTGGGGGAGGCTTAGTGCAGCCCGGAGGGTCCCT GAAACTCTCCTGTGCAACCTCTGGATTCACTTTCAGTGACTATTACATGTATTGGG TTCGCCAGACTCCAGAGAAGAGGCTGGAGTGGGTCGCATACATTAATTCTGGTG GTGGTAGCACCTATTATCCAGACACTGTAAAGGGCCGATTCACCATCTCCAGAGA CAATGCCAAGAACACCCTGTACCTGCAAATGAGCCGGCTGAAGTCTGAGGACAC AGCCATGTATTACTGTGCAAGACGGGGGTTACCGTTCCATGCTATGGACTATTGG GGTCAAGGAACCTCAGTCACCGTCTCCTCAGCCAAAACGAAGGGCCCATCCGTCT TCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCC CTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACT CCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACA CCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGT CCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGGGGGACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAG TTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGG GAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACC AGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCC CGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCAC AGGTGTACACCCTGCCCCCATCCC AGGAGGAGATGACCA AGAACCAGGTCAGCC TGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCG ACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGG AGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACAC ACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGTCAGACCCCCACCAACACC ATCAGCGTGACCCCCACCAACAACAGCACCCCCACCAACAACAGCAACCCCAAG CCCAACCCCGCTAGTCTTCTAACCGAGGTCGAAACGCCGATTCGTAACGAATGGG AGTGCAGATGCAGCGATTCAAGTGATCCTATTGTTGTTGCCGCAAATATCATTGC TAGTGCAGGGGTACCTGAGTCTATGAGGGAAGAGTACCGGCAGGAACAGCAGAG TGCTGTGGATGTTGACGATGGTCATTTTGTCAACATAGAATTGGAGGCTAGTACC GTGACCCCCACCGCCACCGCCACCCCCAGCGCCATCGTGACCACCATCACCCCCA CCGCCACCACCAAGCCCGCTAGCTGA(SEQ ID NO :90)

EcoIi-pET28[Dl-6His-CthermoCohesin-FluMl] [FluMl is shown in double underline; CthermoCohesin is shown in single underline; Dl is shown in bold]

M KLLIAAMMAAALAACSQEAKQEVKEAVQAVESDVKDTAMGSSHHHHHHSS

GLVPRGSHMASMDLDAVRIKVDTVNAKPGDTVNIPVRFSGIPSKGIANCDFVYSYDP NVLEIIEIKPGELIVDPNPTKSFDTAVYPDRKMIVFLFAEDSGTGAYAITKDGVFATIV AKV EGAPNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVT fVGDTTEPATPTTPVTTP TTTDDLDAASLLTEVETYVLSIIPSGPLKAEIAORLEDVFAGKNTDLEVLMEWLKTRP ILSPLTKGILGFVFTLTVPSERGLORRRFVONALNGNGDPNNMDKAVKLYRKLKREI TFHGAKEIALSYSAGALASCMGLIYNRMGAVTTEVAFGLVCATCEOIADSOHRSHRO MVTTT PLIRHENRMVLASTTA AMEOMAGSSEOAAEAMDIASOAROMVOAMRTI GTHPSSSAGLKDDLLENLOAYOKRMGVOMORFKCSEO ID NO :91 )

[00209] This shows a cohesin domain preceded by a Pam3-like TLR2-L attachment sequence which can be used to augment antigenicity of DC-targeting vaccines bearing dockerin domains. Antigens can also be added to the C-terminus of the Dl-cohesin structure, in this example it is the FluMl antigen, which is a well conserved antigen for enhancing broadly cross-protective immunity.

ATGAAAAAACTGCTGATTGCCGCCATGATGGCTGCAGCTCTGGCCGCATGCAGCC AGGAAGCCAAACAGGAAGTGAAAGAAGCCGTGCAGGCCGTGGAAAGCGATGTG AAAGATACCGCCATGGGCAGCAGCCATCATCATCATCATCACAGCAGCGGCCTG GTGCCGCGCGGCAGCCATATGGCTAGTATGGATCTGGATGCAGTAAGGATTAAA GTGGACACAGTAAATGCAAAACCGGGAGACACAGTAAATATACCTGTAAGATTC AGTGGTATACCATCCAAGGGAATAGCAAACTGTGACTTTGTATACAGCTATGACC CGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAGTTGACCCGA ATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTATT CCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGT ATTTGCTACGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGT AATCAAATTTGTAGAAGTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAA GACACAGTTCTTTGACGGTGGAGTAAATGTTGGAGATACAACAGAACCTGCAAC ACCTACAACACCTGTAACAACACCGACAACAACAGATGATCTAGATGCAGCTAG CCTTCTAACCGAGGTCGAAACGTACGTTCTCTCTATCATCCCGTCAGGCCCCCTC AAAGCCGAGATCGCACAGAGACTTGAAGATGTCTTTGCAGGGAAGAACACCGAT CTTGAGGTTCTCATGGAATGGCTAAAGACAAGACCAATCCTGTCACCTCTGACTA AGGGGATTTTAGGATTTGTGTTCACGCTCACCGTGCCCAGTGAGCGGGGACTGCA GCGTAGACGCTTTGTCCAAAATGCTCTTAATGGGAACGGAGATCCAAATAACAT GGACAAAGCAGTTAAACTGTATAGGAAGCTTAAGAGGGAGATAACATTCCATGG GGCCAAAGAAATAGCACTCAGTTATTCTGCTGGTGCACTTGCCAGTTGTATGGGC CTCATATACAACAGGATGGGGGCTGTGACCACTGAAGTGGCATTTGGCCTGGTAT GCGC AACCTGTGAACAGATTGCTGACTCCCAGCATCGGTCTCATAGGCAAATGGT GACAACAACCAATCCACTAATCAGACATGAGAACAGAATGGTTCTAGCCAGCAC TACAGCTAAGGCTATGGAGCAAATGGCTGGATCGAGTGAGCAAGCAGCAGAGGC CATGGATATTGCTAGTCAGGCCAGGCAAATGGTGCAGGCGATGAGAACCATTGG GACTCATCCTAGCTCCAGTGCTGGTCTAAAAGATGATCTTCTTGAAAATTTGCAG GCTTACCAGAAACGGATGGGGGTGCAGATGCAGCGATTCAAGCTCGAGTGA(SEQ ID NO :92)

Anti-LOX-1 15C4H-LV-hIgG4H-C

ATGGGAGGGATCTGGATCTTTCTCTTCCTCCTGTCAGGAACTGCAGGTGCCCACT CTGAGATCCAGCTGCAGCAGACTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAG TGAAGATATCCTGCAAGGCTTCTGGTTATCCATTCACTGACTACATCATGGTCTG GGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGAAATATTAGTCCTTA CTATGGTACTACTAACTACAATCTGAAGTTCAAGGGCAAGGCCACATTGACTGTA GACAAATCTTCCAGCACAGCCTACATGCAGCTCAACAGTCTGACATCTGAGGACT CTGCAGTCTATTACTGTGCAAGATCCCCTAACTGGGACGGGGCCTGGTTTGCTCA CTGGGGCCAAGGGGCTCTGGTCACTGTCTCTGCAGCCAAAACAAAGGGCCCATC CGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTG GGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAG GCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACT CTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACC TACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTT GAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGGGG GACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCG GACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGT CCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCC GCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCT GCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGG CCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA GCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGT CAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGG GAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGC AGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTA CACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGCTGATTAATTAA(SEQ ID NO: 122) Anti-LOX-1 15C4H-LV-hIgG4H-C

MGGIWIFLFLLSGTAGAHSEIQLQQTGPELVKPGASVKISCKASGYPFTDYIMVWVK QSFIGKSLEWIGNISPYYGTTNYNLKFKGKATLTVDKSSSTAYMQLNSLTSEDSAVYY CARSPNWDGAWFAHWGQGALVTVSAAKTKGPSVFPLAPCSRSTSESTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDH PSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLM1SRTPEVTCVVVD VSQEDPEVQFNWYVDGVEVFINAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALH HYTQKSLSLSLGKAS (SEQ ID NO: 123)

Anti-Dectin_l_15E2.5_H-V-hIgG4H-C

ATGGAAAGGCACTGGATCTTTCTACTCCTGTTGTCAGTAACTGCAGGTGTCCACT CCCAGGTCCAGCTGCAGCAGTCTGGGGCTGAACTGGCAAGACCTGGGGCCTCAG TGAAGATGTCCTGCAAGGCTTCTGGCTACACCTTTACTACCTACACTATGCACTG GGTAAAACAGAGGCCTGGACAGGGTCTGGAATGGATTGGATACATTAATCCTAG CAGTGGTTATACTAATTACAATCAGAAGTTCAAGGACAAGGCCACATTGACTGC AGACAAATCCTCCAGCACAGCCTCCATGCAACTGAGCAGCCTGACATCTGAGGA CTCTGCAGTCTATTACTGTGCAAGAGAGAGGGCGGTATTAGTCCCCTATGCTATG GACTACTGGGGTCAAGGAACCTCAGTCACCGTCTCCTCAGCCAAAACAAAGGGC CCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCG CCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAA CTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGA AGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGA GAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGA AGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATC TCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCC GAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACC GTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAAC AAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAAC CAGGTCAGCCTGACCTGCCTGGTC AAAGGCTTCTACCCC AGCGACATCGCCGTGG AGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAG GTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGCTGA (SEQ ID NO: 124)

Anti-Dectin_l_15E2.5_H-V-hIgG4H-C

MERHWIFLLLLSVTAGVHSQVQLQQSGAELARPGASVKMSCKASGYTFTTYTMHW VKQRPGQGLEWIGYINPSSGYTNYNQKFKDKATLTADKSSSTASMQLSSLTSEDSAV YYCARERAVLVPYAMDYWGQGTSVTVSSAKTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT TYTCNV DHKPSNT VD RVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSD IAVEWESNGQPENYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALH NHYTQKSLSLSLGKAS (SEQ ID NO: 125)

Anti-CD40_12E12.3F3_H-V-hIgG4H-C

ATGAACTTGGGGCTCAGCTTGATTTTCCTTGTCCTTGTTTTAAAAGGTGTCCAGTG TGAAGTGAAGCTGGTGGAGTCTGGGGGAGGCTTAGTGCAGCCTGGAGGGTCCCT GAAACTCTCCTGTGCAACCTCTGGATTCACTTTCAGTGACTATTACATGTATTGGG TTCGCCAGACTCCAGAGAAGAGGCTGGAGTGGGTCGCATACATTAATTCTGGTG GTGGTAGCACCTATTATCCAGACACTGTAAAGGGCCGATTCACCATCTCCAGAGA CAATGCCAAGAACACCCTGTACCTGCAAATGAGCCGGCTGAAGTCTGAGGACAC AGCCATGTATTACTGTGCAAGACGGGGGTTACCGTTCCATGCTATGGACTATTGG GGTCAAGGAACCTCAGTCACCGTCTCCTCAGCCAAAACGAAGGGCCCATCCGTCT TCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCC CTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACT CCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACA CCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGT CCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGGGGGACC ATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACC CCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAG TTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGG GAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACC AGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCC CGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCAC AGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCC TGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCG ACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGG AGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACAC ACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGCTGA (SEQ ID NO: 126)

Anti-CD40_12E12.3F3_H-V-hIgG4H-C

MNLGLSLIFLVLVLKGVQCEVKLVESGGGLVQPGGSLKLSCATSGFTFSDYYMYWV RQTPEKRLEWVAYINSGGGSTYYPDTVKGRFTISRDNAKNTLYLQMSRLKSEDTAM YYCARRGLPFHAMDYWGQGTSVTVSSAKTKGPSVFPLAPCSRSTSESTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDH KPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSQEDPEVQFNWYVDGVEVFINAKT PREEQFNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHN HYTQKSLSLSLGKAS(SEQ ID NO: 127)

Anti-LOX-1 15C4K-LV-hIgGK-C

ATGGAGACAGACACAATCCTGCTATGGGTGCTGCTGCTCTGGGTTCCAGGCTCCA CTGGTGACATTGTGCTGACCCAATCTCCAGCTTCTTTGGCTGTGTCTCTAGGGCAG AGGGCCACCATCTCCTGCAAGGCCAGCCAAAGTGTTGATTATGATGGTGATAGTT ATATGAACTGGTTCCAACAGAAACCAGGACAGCCACCCAAACTCCTCATCTATGC TGCATCCAATCTAGAATCTGGGATCCCAGCCAGGTTTAGTGGCAGTGGGTCTGGG ACAGACTTCACCCTCAACATCCATCCTGTGGAGGAGGAGGATGCTGCAACCTATT ACTGTCAGCAAAGTAATGAGGATCCATTCACGTTCGGCTCGGGGACAAAGCTCG AGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGA GCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCC AGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCC CAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAG CACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTATGCCTGCGA AGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGA GTGTTAG(SEQ ID NO: 128)

Anti-LOX-1 15C4K-LV-hIgGK-C

METDTILLWVLLLWVPGSTGDIVLTQSPASLAVSLGQRATISCKASQSVDYDGDS YM NWFQQKPGQPPKLLIYAASNLESGIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQS NEDPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWK VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGEC(SEQ ID NO: 129)

Anti-Dectin_l_15E2.5_K-V-hIgGK-C

ATGCATTTTCAAGTGCAGATTTTCAGCTTCCTGCTAATCAGTGCCTCAGTCATAAT

GTCCAGAGGACAAATTGTTCTCACCCAGTCTCCAGCAGTCATGTCTGCATCTCCA

GGGGAGAAGGTCACCATAACCTGCACTGCCAGCTCAAGTTTAAGTTACATGCACT GGTTCCAGCAGAAGCCAGGCACTTCTCCCAAACTCTGGCTTTATAGCACATCCAT CCTGGCTTCTGGAGTCCCTACTCGCTTCAGTGGCAGTGGATCTGGGACCTCTTACT CTCTCACAATCAGCCGAATGGAGGCTGAAGATGCTGCCACTTATTACTGCCAGCA AAGGAGTAGTTCCCCATTCACGTTCGGCTCGGGGACAAAGCTCGAGATCAAACG AACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAA TCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCA AAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTG TCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGC TGAGCAAAGCAGACTACGAGAAACACAAAGTCTATGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG(SEQ ID NO:130)

Anti-Dectin _1_15E2.5_K-V-hIgGK-C

MHFQVQIFSFLLISASVIMSRGQIVLTQSPAVMSASPGEKVTITCTASSSLSYMHWFQQ KPGTSP LWLYSTSILASGVPTRFSGSGSGTSYSLTISRMEAEDAATYYCQQRSSSPFT FGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGE

C(SEQ ID NO: 131)

Anti-CD40_12E12.3F3_K-LV-hIgGK-C:

ATGATGTCCTCTGCTCAGTTCCTTGGTCTCCTGTTGCTCTGTTTTCAAGGTACCAG ATGTGATATCCAGATGACACAGACTACATCCTCCCTGTCTGCCTCTCTAGGAGAC AGAGTCACCATCAGTTGCAGTGCAAGTCAGGGCATTAGCAATTATTTAAACTGGT ATCAGCAGAAACCAGATGGAACTGTTAAACTCCTGATCTATTACACATCAATTTT ACACTCAGGAGTCCCATCAAGGTTCAGTGGCAGTGGGTCTGGGACAGATTATTCT CTCACCATCGGCAACCTGGAACCTGAAGATATTGCCACTTACTATTGTCAGCAGT TTAATAAGCTTCCTCCGACGTTCGGTGGAGGCACCAAACTCGAGATCAAACGAA CTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCT GGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAG TACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCA CAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGA GCAAAGCAGACTACGAGAAACACAAAGTCTATGCCTGCGAAGTCACCCATCAGG GCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG(SEQ ID NO: 132) Anti-CD40_12E12.3F3_K-LV-hIgG -C

MMSSAQFLGLLLLCFQGTRCDIQMTQTTSSLSASLGDRVTISCSASQGISNYLNWYQ QKPDGTVKLLIYYTSILHSGVPSRFSGSGSGTDYSLTIGNLEPEDIATYYCQQFNKLPP TFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC (SEQ ID NO: 133):

Anti-DCIR_ 9E8.1 E3_H- V-hIgG4H-C

ATGAACAGGCTTACTTCCTCATTGCTGCTGCTGATTGTCCCTGCATATGTCCTGTC CCAGGTTACTCTGAAAGAGTCTGGCCCTGGGATATTGCAGCCCTCCCAGACCCTC AGTCTGACTTGTTCTTTCTCTGGGTTTTCACTGAGCACTTCTGGTATGGGTCTGAG CTGGATTCGTCAGCCTTCAGGAAAGGGTCTGGAGTGGCTGGCACACATTTACTGG GATGATGACAAGCGCTATAACCCATCCCTGAAGAGCCGGCTCACAATCTCCAAG GATACCTCCAGCAACCAGGTTTTCCTCAAGATCACCATTGTGGACACTGCAGATG CTGCCACATACTACTGTGCTCGAAGCTCCCATTACTACGGTTATGGCTACGGGGG ATACTTCGATGTCTGGGGCGCAGGGACCACGGTCACCGTCTCCTCAGCCAAAACG AAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCA CAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTC GTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAG TCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGG GCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGG ACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGA GTTCGAAGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTC ATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAA GACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCC AAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTC CTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTC TCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGG CAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACC AAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGC AATGGGCAGCCGG AGAAC AACTAC AAGACC ACGCC TCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGAC AAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCT CTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAAGCTAGCT GA(SEQ ID NO: 134):

Anti-DCIR_9E8.1E3_H-V-hIgG4H-C

MNRLTSSLLLLIVPAYVLSQVTL ESGPGILQPSQTLSLTCSFSGFSLSTSGMGLSWIR QPSGKGLEWLAHIYWDDDKRYNPSLKSRLTISKDTSSNQVFLKITIVDTADAATYYC ARSSHYYGYGYGGYFDVWGAGTTVTVSSAKTKGPSVFPLAPCSRSTSESTAALGCL VKDYFPEPVTVSW SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV DHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKE Y CKVSN GLPSSIEKTIS AKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEAL HNHYTQKSLSLSLGKAS(SEQ ID NO: 135) Anti-Langerin 15B 10H-LV-hIgG4H-C

ATGGAATGGAGGATCTTTCTCTTCATCCTGTCAGGAACTGCAGGTGTCCACTCCC AGGTTCAGCTGCGGCAGTCTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAGTGA AGATGTCCTGCAAGGCTTCTGGATACACATTTACTGACTATGTTATAAGTTGGGT GAAGCAGAGAACTGGACAGGGCCTTGAGTGGATTGGAGATATTTATCCTGGAAG TGGTTATTCTTTCTACAATGAGAACTTCAAGGGCAAGGCCACACTGACTGCAGAC AAATCCTCCACCACAGCCTACATGCAGCTCAGCAGCCTGACATCTGAGGACTCTG CGGTCTATTTCTGTGCAACCTACTATAACTACCCTTTTGCTTACTGGGGCCAAGGG ACTCTGGTCACTGTCTCTGCAGCCAAAACAACGGGCCCATCCGTCTTCCCCCTGG CGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCA AGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCA GCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAG CAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAA CGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATA TGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCGAAGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGG TCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACT GGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAG CAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCT CCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGT ACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCT GCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATG GGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCT CCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAA GAGCCTCTCCCTGTCTCTGGGTAAAGC AGCTGA(SEQ ID NO: 136) Anti-Langerin 15B 10H-LV-hIgG4H-C

QVQLRQSGPELVKPGASV MSCKASGYTFTDYVISWVKQRTGQGLEWIGDIYPGSG YSFYNENFKGKATLTADKSSTTAYMQLSSLTSEDSAVYFCATYYNYPFAYWGQGTL VTVSAAKTTGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQS SGL YSLS S V VTVPS S SLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPA PEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVF1NAK T PREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE TISKAKGQPRE PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENYKTTPPVLDSDGS FFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKAS(SEQ ID NO:137)

Anti-DCIR 9E8.1 E3_K-LV-hIgGK-C

ATGGAGACAGACACACTCCTGCTATGGGTGCTGCTGCTCTGGGTTCCAGGTTCCA

CAGGTAACATTGTGCTGACCCAATCTCCAGCTTCTTTGGCTGTGTCTCTAGGGCA

GAGGGCCACCATATCCTGCAGAGCCAGTGAAAGTATTCATAGTTATGGCAATAG TTTTCTGCACTGGTACCAGCAGAAACCAGGACAGCCACCCAAACTCCTCATCTAT CTTGCATCCAACCTAGAATCTGGGGTCCCTGCCAGGTTCAGCGGCAGTGGGTCTA GGACAGACTTCACCCTCACCATTGATCCTGTGGAGGCTGATGATGCTGCAACCTA TTACTGTCAGCAAAATAATGAGGATCCGTGGACGTTCGGTGGAGGCACCAAGCT CGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGAT GAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATC CCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACT CCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCA GCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTATGCCTGCG AAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAG AGTGTTAGGCGGCCGCACTAGCGCGGGCCGCATTCGAAGAGCTCGGTACCCGGG GATCCTCTAGAGTCGACCTGCAGGCATGCAAGCTGGCCGCGACTCTAGATCATAA TCAGC(SEQ ID NO: 138)

Anti-DCIR 9E8.1 E3_K-LV-hIgGK-C

METDTLLLWVLLLWVPGSTGNIVLTQSPASLAVSLGQRATISCRASESIHS YGNSFLH WYQQ PGQPPKLLIYLASNLESGVPARFSGSGSRTDFTLTIDPVEADDAATYYCQQN NEDPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNFYPREA VQWK VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH VYACEVTHQGLSSPVT KSFNRGEC(SEQ ID NO: 139)

Anti-Langerin 15B 1 OK-LV-hlgGK-C

ATGAAGTTGCCTGTTAGGCTGTTGGTGCTGATGTTCTGGATTCCTGCTTCCAGCAG

TGATGTTGTGATGACCCAAACTCCACTCTCCCTGCCTGTCCGTCTTGGAGATCAA

GCCTCCATCTCTTGCAGATCTAGTCAGAGCCTTGTACACAGTAATGGAAACACCT ATTTACATTGGTACCTGCAGAAGCCAGGCCAGTCTCCAAAGCTCCTGATCTACAA AGTTTCCAACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGG ACAAATTTCACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGACTTTATT TCTGCTCTCAAAGTACACATGTTCCGTACACGTTCGGAGGGGGGACCAAGCTCGA GATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAG CAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCA GAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCC AGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGC ACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTATGCCTGCGAA GTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAG TGTTAG(SEQ ID NO: 140)

Anti-Langerin 15B 10K-LV-hIgG -C

DVVMTQTPLSLPVRLGDQASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVS NRFSGVPDRFSGSGSGTNFTLKISRVEAEDLGLYFCSQSTHVPYTFGGGTKLEIKRTV AAPSVFIFPPSDEQLKSGTASVVCLLN FYPREAKVQWKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT SFNRGEC (SEQ ID NO:141)

Modular Domain Description of DC-targeting influenza vaccines [00210] In certain aspects a DC targeting influenza vaccine may be assembeled by combining polypeptides domains belonging to various classes of proteins categorized according to a specific function. In a general sense these domains may belong to classes comprising antibodies, antibody CDRs, antibody heavy chains, antibody light chains, linkers, antigens, coupling domains, adjuvants, purification tags, labelling tags or reporter tags. [00211] Non limiting examples of domain categories and specific examples within each category are illustrated in Table 1. (Flgln is abbreviation for Flagellin)

Table 1.

[00212] In some embodiments, components of a DC-targeting vaccine may be constructed as illustrated below (For the schematic represenations that follow, the following abbreviations apply : Peptide Linker (PL); Antigen (Ag); Tag (Tg); Coupling Domain (CD); Adjuvant (Adj); Antibody (Ab). A number following an abbreviation differentiates between different types of that domain within a construct) :

CD-Ag-Tg;

Ab-Ag-Tg;

Ab-CD-Ag-Tg;

Ab-PL-Ag; Ab-PL-Ag-Tg;

Ab-PL-Ag(l )-Ag(2)-Tg;

Ab-CD-PL;

Ab-Ag;

Tg-CD-Ag;

Tg-CD-Ag-Tg;

Ab-Adj;

Ab-Adj-Adj;

Tg-CD-Adj;

Tg-CD-Adj(l)-Adj(2);

CD-Adj;

Ab-PL-Ag-PL-Ag;

PL includes but is not limited to peptide linkers. Linkers with non-peptide bonds are also contemplated. In some embodiments the tag is absent from the construct or has been removed.

[00213] In one particular embodiment, an antibody-antigen fusion protein

(Ab.Ag) comprises the following formula:

Ab-(PL-Ag)x;

Ab-(Ag-PL)x; Ab-(PL-Ag-PL)x;

Ab-(Ag-PL-Ag)x;

Ab-(PL-Ag)x-PL; or

Ab-(Ag-PL)x-Ag; wherein Ab is an DC targeting antibody or a fragment thereof; wherein PL is a peptide linker; wherein Ag is an Influenza antigen; and, wherein x is an integer from 1 to 20, or any range derivable therein. PL includes but is not limited to peptide linkers. Linkers with non-peptide bonds are also contemplated.

[00214] In one embodiment, the -(PL-Ag)x, -(Ag-PL)x, -(PL-Ag-PL)x, or -

(Ag-PL-Ag)x are located at the carboxy terminus of the Ab heavy chain or fragment thereof. [00215] In another embodiment, the -(PL-Ag)x, -(Ag-PL)x, -(PL-Ag-PL)x, or -

(Ag-PL-Ag)x are located at the carboxy terminus of the Ab light chain or fragment thereof.

[00216] In one embodiment, the antibody-antigen complex (Ab:Ag) comprises the following formula

Ab.Doc:Coh.Ag; Ab.Coh:Doc.Ag;

Ab.(Coh)x:(Doc.Ag)x;

Ab.(Doc)x:(Coh.Ag)x;

Ab.(Coh.Doc)x:(Doc.Ag ¹ )(Coh.Ag ² ); or

Ab.(Coh)x(Doc)x:(Doc.Ag ^] )x(Coh.Ag ² )x; wherein Ab is a DC targeting antibody or a fragment thereof; wherein Ag is an

Influenza antigen (Ag ¹ and Ag ² being two distinct Influenza antigens); wherein Doc is Dockerin; wherein Coh is Cohesin and wherein x is an integer from 1 to 10, or any range derivable therein.

IV. METHODS OF TREATMENT

[00217] As discussed above, the compositions and methods of using these compositions can treat a subject (e.g. , prevent an Influenza infection or evoke a robust immune response to Influenza) having, suspected of having, or at risk of developing an infection or related disease, particularly those related to Influenza (also referred to as flu or seasonal flu). [00218] As used herein the phrase "immune response" or its equivalent

"immunological response" refers to a humoral (antibody mediated), cellular (mediated by antigen-specific T cells or their secretion products) or both humoral and cellular response directed against a protein, peptide, or polypeptide of the invention in a recipient patient. Treatment or therapy can be an active immune response induced by administration of immunogen or a passive therapy effected by administration of antibody, antibody containing material, or primed T-cells.

[00219] For purposes of this specification and the accompanying claims the terms "epitope" and "antigenic determinant" are used interchangeably to refer to a site on an antigen to which B and/or T cells respond or recognize. B-cell epitopes can be formed both from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed from contiguous amino acids are typically retained on exposure to denaturing solvents whereas epitopes formed by tertiary folding are typically lost on treatment with denaturing solvents. An epitope typically includes at least 3, and more usually, at least 5 or 8-10 amino acids in a unique spatial conformation. Methods of determining spatial conformation of epitopes include those methods described in Epitope Mapping Protocols (1996). T cells recognize continuous epitopes of about nine amino acids for CD8 cells or about 13-15 amino acids for CD4 cells. T cells that recognize the epitope can be identified by in vitro assays that measure antigen-dependent proliferation, as determined by 3H-thymidine incorporation by primed T cells in response to an epitope (Burke et al., 1994), by antigen-dependent killing (cytotoxic T lymphocyte assay, Tigges et al., 1996) or by cytokine secretion.

[00220] The presence of a cell-mediated immunological response can be determined by proliferation assays (CD4 (+) T cells) or CTL (cytotoxic T lymphocyte) assays. The relative contributions of humoral and cellular responses to the protective or therapeutic effect of an immunogen can be distinguished by separately isolating IgG and T- cells from an immunized syngeneic animal and measuring protective or therapeutic effect in a second subject. As used herein and in the claims, the terms "antibody" or "immunoglobulin" are used interchangeably.

[00221] Optionally, an antibody or preferably an immunological portion of an antibody, can be chemically conjugated to, or expressed as, a fusion protein with other proteins. For purposes of this specification and the accompanying claims, all such fused proteins are included in the definition of antibodies or an immunological portion of an antibody. [00222] In one embodiment a method includes treatment for a disease or condition caused by the Influenza virus. In certain aspects embodiments include methods of treatment of Influenza, such as an infection acquired from an individual with Influenza. In some embodiments, the treatment is administered in the presence of Influenza antigens. Furthermore, in some examples, treatment comprises administration of other agents commonly used against viral infection, such as one or more antiviral or antiretroviral compounds.

[00223] The therapeutic compositions are administered in a manner compatible with the dosage formulation, and in such amount as will be therapeutically effective. The quantity to be administered depends on the subject to be treated. Precise amounts of active ingredient required to be administered depend on the judgment of the practitioner. Suitable regimes for initial administration and boosters are also variable, but are typified by an initial administration followed by subsequent administrations.

[00224] The manner of application may be varied widely. Any of the conventional methods for administration of a polypeptide therapeutic are applicable. These are believed to include oral application on a solid physiologically acceptable base or in a physiologically acceptable dispersion, parenterally, by injection and the like. The dosage of the composition will depend on the route of administration and will vary according to the size and health of the subject. [00225] In certain instances, it will be desirable to have multiple administrations of the composition, e.g., 2, 3, 4, 5, 6 or more administrations. The administrations can be at 1, 2, 3, 4, 5, 6, 7, 8, to 5, 6, 7, 8, 9 ,10, 1 1, 12 twelve week intervals, including all ranges there between.

Combination Therapy

[00226] The compositions and related methods, particularly administration of an antibody that binds DC receptor and delivers an Influenza antigen or a peptide to a patient/subject, may also be used in combination with the administration of traditional antiretroviral therapies. These include, but are not limited to, entry inhibitors, CCR5 receptor antagonists, nucleoside reverse transcriptase inhibitors, nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors and maturation inhibitors. [00227] In one aspect, it is contemplated that a therapy is used in conjunction with antiviral or anti-retroviral treatment. Alternatively, the therapy may precede or follow the other agent treatment by intervals ranging from minutes to weeks. In embodiments where the other agents and/or a proteins or polynucleotides are administered separately, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that the therapeutic composition would still be able to exert an advantageously combined effect on the subject. In such instances, it is contemplated that one may administer both modalities within about 12-24 h of each other and, more preferably, within about 6-12 h of each other. In some situations, it may be desirable to extend the time period for administration significantly, however, where several days (2, 3, 4, 5, 6 or 7) to several weeks (1 , 2, 3, 4, 5, 6, 7 or 8) lapse between the respective administrations.

[00228] Various combinations of therapy may be employed, for example antiviral therapy is "A" and an antibody vaccine that comprises an antibody that binds a DC receptor and delivers an Influenza antigen or a peptide or consensus peptide thereof is "B": A/B/A B/A/B B/B/A A/A/B A/B/B B/A/A A/B/B/B B/A/B/B

B/B/B/A B/B/A/B A/A/B/B A/B/A/B A/B/B/A B/B/A/A

B/A/B/A B/A/A/B A/A/A/B B/A/A/A A/B/A/A A/A/B/A

[00229] Administration of the antibody compositions to a patient/subject will follow general protocols for the administration of such compounds, taking into account the toxicity, if any, of the composition. It is expected that the treatment cycles would be repeated as necessary. It is also contemplated that various standard therapies, such as hydration, may be applied in combination with the described therapy.

General Pharmaceutical Compositions

[00230] In some embodiments, pharmaceutical compositions are administered to a subject. Different aspects may involve administering an effective amount of a composition to a subject. In some embodiments, an antibody that binds DC receptor and delivers an Influenza antigen or a peptide or consensus peptide thereof may be administered to the patient to protect against or treat infection by one or more Influenza subtypes. Alternatively, an expression vector encoding one or more such antibodies or polypeptides or peptides may be given to a patient as a preventative treatment. Additionally, such compositions can be administered in combination with an antibiotic or antiviral agent. Such compositions will generally be dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium.

[00231] The phrases "pharmaceutically acceptable" or "pharmacologically acceptable" refer to molecular entities and compositions that do not produce an adverse, allergic, or other untoward reaction when administered to an animal or human. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredients, its use in immunogenic and therapeutic compositions is contemplated. Supplementary active ingredients, such as other anti-infective agents and vaccines, can also be incorporated into the compositions.

[00232] The active compounds can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as either liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and, the preparations can also be emulsified. [00233] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[00234] The proteinaceous compositions may be formulated into a neutral or salt form. Pharmaceutically acceptable salts, include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.

[00235] A pharmaceutical composition can include a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. [00236] Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization or an equivalent procedure. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum- drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[00237] Administration of the compositions will typically be via any common route. This includes, but is not limited to oral, nasal, or buccal administration. Alternatively, administration may be by orthotopic, intradermal, subcutaneous, intramuscular, intraperitoneal, intranasal, or intravenous injection. In certain embodiments, a vaccine composition may be inhaled (e.g. , U.S. Patent 6,651 ,655, which is specifically incorporated by reference). Such compositions would normally be administered as pharmaceutically acceptable compositions that include physiologically acceptable carriers, buffers or other excipients. [00238] An effective amount of therapeutic or prophylactic composition is determined based on the intended goal. The term "unit dose" or "dosage" refers to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of the composition calculated to produce the desired responses discussed above in association with its administration, i.e., the appropriate route and regimen. The quantity to be administered, both according to number of treatments and unit dose, depends on the protection desired.

[00239] Precise amounts of the composition also depend on the judgment of the practitioner and are peculiar to each individual. Factors affecting dose include physical and clinical state of the subject, route of administration, intended goal of treatment (alleviation of symptoms versus cure), and potency, stability, and toxicity of the particular composition.

[00240] Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically or prophylactically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above.

Table 2.

TABLE OF EXPERIMENTAL DESIGN AND ANIMAL PROCEDURES

- I l l - 5 FluMist IN 5

5 Control 5

Total number of animals 55

Table 3.

Week 6 Vaccination 2 Vaccination 2

Blood 2-4x 4.9ml EDTA Blood 2-4x 4.9ml EDTA BAL - 15-25ml BAL - 15-25ml

Nasal wash Nasal wash

CBC/Chemistry/PE CBC/Chemistry/PE

Day 3 post vaccination Blood l x 4.9ml EDTA Blood lx 4.9ml EDTA

Week 1 post vaccination 2 Blood 2-4x 4.9ml EDTA Blood 2-4x 4.9ml EDTA

BAL - 15-25ml BAL - 15-25ml

Nasal wash Nasal wash

Nasal Biopsy Nasal Biopsy

LN LN

Duodenal Biopsies Duodenal Biopsies

CBC/Chemistry/PE CBC/Chemistry/PE

Every 1-2 Weeks Blood 2-4x 4.9ml EDTA Blood 2-4x 4.9ml EDTA

BAL - 15-25ml BAL - 15-25ml

Nasal wash Nasal wash

Week 14 Vaccination 3 Vaccination 3

Blood 2-4x 4.9ml EDTA Blood 2-4x 4.9ml EDTA BAL - 15-25ml BAL - 15-25ml

Nasal wash Nasal wash

CBC/Chemistry/PE CBC/Chemistry/PE

Day 3 post vaccination Blood lx 4.9ml EDTA Blood lx 4.9ml EDTA

Week 1 post vaccination 3 Blood 2-4x 4.9ml EDTA Blood 2-4x 4.9ml EDTA

BAL - 15-25ml BAL - 15-25ml

Nasal wash Nasal wash

Nasal Biopsy Nasal Biopsy

LN LN

Duodenal Biopsies Duodenal Biopsies

CBC/Chemistry/PE CBC/Chemistry/PE

Every 1-2 Weeks Blood 2-4x 4.9ml EDTA Blood 2-4x 4.9ml EDTA

BAL - 15-25ml BAL - 15-25ml

Nasal wash Nasal wash

CBC/Chemistry/PE CBC/Chemistry/PE

Week 1 or 2 post Vaccination 4-6 (doses will Week 1 or 2 post vaccination 3 protocol be determined following vaccination 3 protocol

previous vaccination)

Blood 2-4x 4.9ml EDTA

CBC/Chemistry/PE

Week 1 post vaccination Blood lx 4.9ml EDTA Week 1 post vaccination

Week 2 or 3 post Blood 2-4.9ml EDTA Week 2 or 3 post vaccination LN vaccination

CBC/Chemistry/PE

Week 1-2 following last Virus challenge Virus challenge

vaccination protocol Blood 2-4x 4.9ml EDTA Blood 2-4x 4.9ml EDTA

BAL - 15-25ml BAL - 15-25ml

Nasal wash Nasal wash

CBC/Chemistry/PE CBC/Chemistry/PE Days post Challenge Blood 4.9ml EDTA Blood 4.9ml EDTA

3, 5, 7*, 10, 14 *Day 7 - add: *Day 7 - add:

BAL - 15-25ml BAL - 15-25ml

LN LN

Nasal Biopsy Nasal Biopsy

Duodenal Biopsies Duodenal Biopsies

CBC/Chemistry/PE CBC/Chemistry/PE

Every 1-2 Weeks Blood 2-4x 4.9ml EDTA Blood 2-4x 4.9ml EDTA

(Until the end of the BAL - 15 -25 ml BAL - 15-25ml

study) Nasal wash Nasal wash

CBC/Chemistry/PE CBC/Chemistry/PE

IV. Examples

[00241] The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

Example 1 - Materials & Methods

Table of Experimental Design and Animal Vaccine Procedures

[00242] In order to maximize the immune response of vaccinated macaques, we utilized adjuvants used in animals models and in humans: Montanide, poly(I:C) and CpG. Montanide, also known as incomplete Freund's adjuvant (IF A), is a mixture of oil and water that can be combined with a specific antigen to boost the immune response to that antigen. It is being studied in immunotherapy and as a way to increase the immune response to cancer vaccines and has been used in veterinary applications for decades. Many historically reported adverse effects to IFA administration have been alleviated by the use of improved manufacturing processes and refined oils. Poly(I:C) is a synthetic section of double stranded RNA that is known to stimulate cytokine release. CpG is a type of synthetic oligodeoxynucleotide that stimulates B cells and dendritic cells to increase the Thl immune response. Neither poly (I:C) nor CpG is known to cause significant adverse effects in the small amounts used as an adjuvant. In some instances a vaccine boost was utilized to induce a more robust immune response. (See Appendix A for Vaccination Schedule and Methods)

Microarray-based Immunomonitoring of NHP Responses to DC-Targeted Influenza Vaccination and Cal04 Challenge

[00243] At each time point during the vaccination phase (Week 0, 6, 12) and Cal04 Challenge phase (Day -7, 0, 1 , 3, 6, 8, 14, 20) a total of 1.2ml of whole blood was collected into Lithium-Heparin blood collection tubes. Next, 500ul aliquots of blood were mixed with 1.5ml of Tempus reagent to stabilize total RNA (1). Total RNA was isolated from the whole blood lysate using the MagMAX-96 Blood RNA Isolation Kit (Applied Biosystems) according to the manufacturer's instructions. Following extraction an Agilent 2100 Bioanalyzer (Agilent) was used to attain RNA Integrity Numbers (RIN) for each sample. RNA yields were attained using a Nanodrop 8000 (Nanodrop Technologies). Both RIN and yield data were managed using a LIMS system for quality control and sample tracking.

[00244] After RNA extraction and quality control analysis globin mRNA was depleted from a portion of each total RNA sample using the GLOBINclear-Human 96-well format kit (Ambion). This was then followed by another round of RIN and yield determinations for quality control purposes. All samples passing quality control were then amplified and labeled using the Illumina TotalPrep-96 RNA amplification kit (Ambion). The RNA input for this reaction was 250ng and 750ng of amplified labeled RNA was hybridized overnight to Illumina HT12 V4 beadchips (Illumina). Each chip was washed, blocked, stained, and scanned on an Illumina iScan following the manufacturers protocols. Illumina's Genome Studio software was used to generate signal intensity values from each scanned array, subtract background signal, and scale each microarray to the median average intensity for all samples. The approach of using Illumina human arrays to assess NHP responses has been previously reported (2). After identifying those probes expressed in at least one sample we visualized the data using Genespring 7.3 software. All vaccination phase samples were normalized to Week 0 samples from each experimental group while all challenge phase samples were normalized to Day -7 and 0 controls. Linear Mixed Modeling using JMP Genomics 6.0 (SAS) was employed to identify genes with differential abundance in both longitudinal and cross-sectional comparisons. GeneGo and Ingenuity Pathway Analysis software was used for the functional annotation of these gene lists thus identifying gene networks and pathways with differential activity between sample groups. Microarray protocols are described in Fukazawa, Y. et a., et al. (2012) the contents of which are incorporated herein by reference.

Example 2 - Anti-DC receptor Influenza NP vaccines

[00245] Alignment between two NP sequences from Nl flu strains highlights the high conservation (in this case 91.6% identity). Conservation extends to homology between Nl and N5 strains (e.g., 93.4% identity between NP-1 and NP-5 sequences). This feature makes NP an attractive antigen for universal influenza vaccine development (Fig. 1).

[00246] 4 different anti-DC-receptor antibody-NP antigen fusion proteins (with NP appended to the H chain) were made and purified (Fig. 2, leftmost panel). These were produced in CHO-S cells as secreted products and were purified via protein A affinity chromatography. They are show stained by Coomassie brilliant blue after running on reduced SDS-PAGE. A schematic for testing the efficacy of such vaccines to expand memory NP- specific CD8+ T cells in culture via delivery to autologous DCs is illustrated (Fig. 2, middle panel). After a several day culture period, the culture is stimulated with pools of NP-specific peptides and 48h later culture supernatants are tested for T cell cytokines. In this example the donor had memory cells to peptides in several pools as indicated by the increase in IFNgamma production compared to non-peptide control (Fig. 2, rightmost panel). This test is an in vitro analog of what is expected via in vivo delivery of such a vaccine - i.e., expansion of memory NP-specific CD8+ T cells which are potentially protective of a renewed influenza infection. CD4+ T cells (helpers) would be expanded in a similar manner to help both CD8+ T cell and B cell responses specific to NP.

[00247] Timeline of vaccination schedule in Rhesus macaques for testing the efficacy of DC-targeting (via delivery by anti-CD40, anti-Dectin-1 , and anti-LOX-1) is provided. In this example, three doses given ID of 100 micrograms each are given with Poly ICLC as adjuvant. The animals are rested and then challenged with live influenza virus carrying the homologous NP protein. Blood samples are taken as indicated for the analyses listed (Fig. 3).

[00248] Results of live virus challenge of naive NHP as appraised by IFNg-

ELISPOT analysis of HA-specific T cell responses in the circulation shows that live virus challenge elicits HA-specific T cell responses which are detectable as soon as day 8 after virus challenge. In these experiments each spot pair represents an NHP. (Fig. 4). Anti-CD3 is the positive control (triangle; polyclonal stimulation), HA-specific responses are read by addition of HA peptide pools and/or HA fusion proteins (shown here in upside-down triangle and open square), while the background controls of peptide solvent without peptide and fusion partner without HA are diamond and circle. Frozen PBMCs 4 hrs incubation in medium, then stimulated with HA1 peptide pools, or HA1 protein, and controls on ELISPOT plates for 36 hr (Fig. 4)

[00249] Results of live virus challenge of naive NHP as appraised by IFNg-

ELISPOT analysis of NP-specific T cell responses in the circulation shows that live virus challenge elicits NP-specific T cell responses which are detectable as soon as day 8 after virus challenge. In these experiments each spot pair represents on NHP. (Fig. 5). Live HlNl challenge elicits circulating T cell responses specific to HA1 and NP antigens which are detectable at D8 post-challenge. Anti-CD3 is the positive control (triangle; polyclonal stimulation), NP-specific responses are read by addition of NP peptide pools and/or NP fusion proteins (shown here in upside-down triangle and open square), while the background controls of peptide solvent without peptide and fusion partner without NP are diamond and circle.

[00250] PBMC IFNg-ELISPOT analysis of circulating NP-specific T cells in response to vaccination by anti-CD40-NP-5 fusion protein with co-administered Poly ICLC shows that vaccine elicits robust T cell response specific to NP, which are maintained for at least 5 weeks after the last vaccine (12 weeks) (Fig. 6, upper triangles are the anti-CD3 positive controls, the filled square, filled triangle, and diamond are the NP stimulations with peptide or NP fusion protein, while the circles and upside down triangle are background controls) In NHP vaccinated with anti-CD40-NP, NP-specific T cell responses are elicited which are maintained for at least 5 weeks. Live HlNl challenge boosts the NP-specific T cells between D 14 and D20 post challenge.

[00251] Kinetics of development in naive NHP vs. anti-CD40-NP vaccinated

NHP of HA-specific T cell responses from live influenza challenge as determined by IFNg- ELISPOT analysis of circulating blood cells (PBMC) show that vaccination of na ^' ive NHP with aCD40-NP/poly ICLC may delay development of anti-HAl -specific T cell responses elicited by live virus challenge (Fig. 7). [00252] Analysis via ELISA of serum levels of anti-NP-specific IgG antibodies show the development of robust levels of potentially protective anti-NP antibody levels which are significantly and rapidly boosted by live influenza virus challenge (Fig.8). Levels are expressed as ED50 derived from titration curves. Each square is a value from an individual NHP. Vaccination of nai ^' ve NHP with 3x 100 mg aCD40-NP/poly ICLC vaccines evokes significant and lasting (> 5 weeks) NP-specific B cell responses which are further boosted by live virus challenge (Fig. 8).

[00253] Analysis via ELISA of serum levels of anti-NP-specific IgG antibodies show the development of robust levels of potentially protective anti-NP antibody levels which are significantly and rapidly boosted by live influenza virus challenge (Fig. 9). Levels are expresses as ED50 derived from titration curves. Each square is a value from an individual NHP. Vaccination of naive NHP with 3x 100 mg antiDC receptor antibody- NP/poly ICLC vaccines targeting CD40, LOX-1 and Dectin-1 evokes significant and lasting (> 5 weeks) NP-specific B cell responses which are boosted by live virus challenge. All three vaccines are equipotent by this test. (Fig. 9)

[00254] Antigen-specific antibody analysis of a control NHP group which received Poly ICLC alone and was then challenged with live influenza virus shows NP and HA-specific antibody responses are detected at day 8 and increase through day 20 in this representative NHP (Fig. 10). [00255] Analysis of blood mRNA illustrates changes via microarray. The phase

1 media alone data are from NHP which are treated with buffer without virus. The phase 2 data are from the same NHP treated with live or UV inactivated virus as indicated. Gene mRNA levels are normalized to the day -1 time points. The data show striking blood mRNA changes (increases are above and decreased are below the normalization points and are on a log base 10 scale, Fig. 1 1 )). The changes are maximal at day 1 (early response) and at day 5 (late response, presumably due to extended viral replication). Note that changes in the killed virus group are minimal. In the group vaccinated with DC-targeting vaccines carrying NP and HA antigens with CpG as adjuvant and rested for several months, the early phase is apparently unaltered, but the late phase changes are minimized (Fig. 1 1). [00256] Microarray analyses from live virus challenge of three NHP groups receiving DC-targeting vaccines bearing NP-5 antigen show that the late day 5-6 mRNA changes characteristic of live virus challenge are significantly modulated by the vaccinations (Fig. 12). In particular, in the anti-CD40-NP-5 vaccinated group, the early responses also appear to be reduced. The virus used in the experiments is an HlNl virus, which is therefore heterologous with respect to the antigen. Example 3 - NHP DC-targeting Influenza HAl + Poly ICLC vaccine studies

[00257] IFN gamma ELISPOT assay demonstrates that NHP CD40-targeting influenza HAl + Poly ICLC vaccine elicits an HA specific, but not an NP5, immune response during the vaccination protocol. Challenge with HlNl live virus evidences both an HA and NP5 immune response; kinetics of HAl response is faster than NP5 upon challenge for HAl vaccinated animals (Fig. 14).

[00258] Anti-CD40-HA1 + Poly ICLC vaccine elicits high serum anti-HA antibody titers after 1 boost (Fig. 15). Titers of HAl antibodies wane somewhat over the 5 week rest. Subsequent challenge with live virus increases HAl titers to post vaccine levels (Fig. 15). [00259] Anti-CD40-HA1, anti-Dectin-HA-1 and anti-LOX-HAl elicit high serum anti-HAl antibody titers after 1-2 boosts. Antibody titers for all three vaccines wane over 5 week interval between vaccination and live influenza challenge. Subsequent challenge with live HlNl virus increases titers to post vaccine levels (Fig. 16).

[00260] In contrast to FluZone and Poly ICLC alone, the three DC-targeting HAl vaccines elicit and sustain robust blood HAl titers that are not affected by live virus challenge (Fig. 17).

[00261] Targeting-HA and Poly ICLC injection results in a signature perturbation 6 weeks following vaccination and reduction of both Day 1 and Day 6 responses to Cal04 challenge (Fig. 18). [00262] Targeting-HA polypeptides were recombinantly fused to fiagellin and used in NHP influenza vaccine studies (Fig. 19).

[00263] Anti-CD40-HA-Flagellin vaccine elicits earlier, more robust and more sustained serum anti-HAl titers than anti-Dectin-1 -HAl -Fiagellin or anti-LOX-l -HAl - Fiagellin (Fig. 20). [00264] Anti-DC receptor HAl -Flagellin vaccines elicit only modest anti-

Flagellin antibody titers that rapidly wane (Fig. 21).

[00265] In NHP vaccine studies with DC-targeting influenza HAl -Flagellin, 3 of 4 NHP receiving CD-40-targeting HAl -Flagellin vaccine demonstrated robust HAl titers that were not affected by challenge with live HlNl . Rank order of efficacy is anti-CD40 > anti-Dectin-1 > antiLox-1 > Poly ICLC alone (Fig. 22).

[00266] In NHP vaccine studies with DC-targeting influenza HAl -Flagellin, 3 of 4 NHP receiving CD-40-targeting HAl-Flagellin vaccine demonstrated robust blood micro-neutralization titers that were boosted by challenge with live HlNl . Rank order of efficacy is anti-CD40 > anti-Dectin-1 > antiLox-1 > Poly ICLC alone (Fig. 23).

[00267] In NHP vaccine studies with DC-targeting influenza HAl -Flagellin, targeting-HA-Flagellin vaccines attenuate mRNA changes from live virus challenge (Fig. 24). A secondary change in mRNA expression evident in control NHP challenged with live HlNl (Fig. 1 1, uppermost panel) is absent from NHP receiving targeting-HA-Flagellin vaccines (Fig. 24).

[00268] In NHPs primed with live HlNl, administration of 100 micrograms of anti-Dectin-1 -NP + Poly ICLC evidences a strong and specific NP5 serum IgG response (Fig. 25, upper left panel). HAl serum IgG levels for animals with this condition do not evidence a change with administration of anti-Dectin-1 -NP + Poly ICLC (Fig. 25, upper right panel). Similarly, In NHPs primed with live HlNl , administration of 100 micrograms of anti-Dectin- 1 -NP without Poly ICLC evidences a strong and specific NP5 serum IgG response (Fig. 25, lower left panel). HAl serum IgG levels in animals treated with anti-Dectin-1 -NP without Poly ICLC evidence minimal increase (Fig. 25, lower right panel).

[00269] In NHPs primed with live HlNl , administration of anti-Dectin-1 -NP with Poly ICLC yields a robust and steady increase in antibody titers against NP-5 (Fig. 26, upper left panel). Administration of anti-CD40-NP with Poly ICLC yields a similar increase in NP5 titers in live HlNl primed animals (Fig. 26, upper right panel). Antibody titers to NP- 5 demonstrate a greatly reduced increased when animals are primed with a killed HlNl virus (Fig. 26, lower left and lower right panels). Example 4 - Anti-CD40-Flu NP fusion protein can efficiently elicit NP-specific CD8+ T cell responses

[00270] The inventors have tested the ability of CD40 as a receptor for antigen cross-presentation to CD8 ⁺ T cells. CFSE-labeled peripheral blood mononuclear cells (PBMCs) from healthy donors were loaded with recombinant fusion proteins (1 g/ml) (anti- CD40-NP, anti-Dectin-l-NP, and anti-LOX- 1-NP). After 8 days, cells were restimulated with Flu NP peptide pool (1 μΜ) for 6h in the presence of brefeldin A. Intracellular IFNg expression was assessed for CD3+, CD4+, and CD8+ T cells. As shown in Figure 1 , anti- CD40-NP resulted in greater NP-specific IFNg+CD8+ T cell responses than anti-Dectin-1- NP or anti-LOX- 1 -NP did, although anti-CD40-NP resulted in relatively lower NP-specific CD4+ T cell responses compared to anti-Dectin-l-NP and anti-LOX- 1-NP. Taken together, antigen targeting to DCs via CD40 can efficiently elicit antigen-specific CD8+ T cell responses that are crucial immune arm against viral infections. (Fig. 27)

^ [00271] All of the methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

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