Compound for increasing efficacy of viral vectors

The field of present invention relates to compounds for increasing efficiency of non-pathogenic viral vectors, such as used in vaccines or in gene therapy.

Wild-type adeno-associated viruses (AAV) are typically non- pathogenic and only capable of replicating in the presence of helper viruses. One big advantage of this class of viral gene therapy vectors is that they maintain long term, sustained gene expression in the host cell, making them ideal for therapeutic gene delivery. Numerous natural subtypes have been isolated showing serological differences and unique tropism in vivo and in vitro. AAV vectors are well suited for targeting different cell types. Importantly, they typically do not integrate into the genome of the host cell (Colella et al, 2017).

To date, many different serotypes and variants are well studied including AAV2, AAV5 or AAV8. New gene therapy compositions such e.g. Voretigene neparvove (Luxturna®; based on AAV2) or onasemnogene abeparvovec-xioi (Zolgensma®; based on AAV9) were successfully tested and approved, reflecting the dynamic progress in this field. Li (Li et al, 2020) provides an extensive review about AAV vectors. New concepts of improving gene expression, tissue specificity, genome stability, combined with capsid engineering can be found in Domenger (Domenger et al, 2019).

Much effort was invested into engineering improved AAV capsid variants to change their biological properties including tropism and safety. However, susceptibility to antibody neutralization by preexisting antibodies of the patient remains a major challenge, see e.g. Costa Verdera et al, 2020.

Kruzik et al, 2019, investigated the prevalence of neutralizing antibodies against various AAV serotypes in different patient cohorts. It was found, for example, that neutralizing antibodies against AAV2 were most abundant at levels up to 74% of the population. Antibodies against AAV8 were found for example in up to 63%. Natural antibodies against AAV5 (up to 59%) and AAV1 (27%) were less abundant. Interestingly, most people tested exhibited antibodies against more than one serotype. A comprehensive review was published by Ronzitti et al, 2020.

The consequences were for example that a hemophilia B gene therapy trial with an AAV vector turned out to be problematic because of pre-existing neutralizing antibodies against AAV in patients that did not respond to the therapy. Manno et al., 2006, showed for example that even low titers of neutralizing antibodies could block the effectivity of gene therapy by blocking virus function by opsonization.

Tseng et al, 2014, reviewed epitopes of anti-AAV antibodies found with human serum and monoclonal antibodies. The interaction between preexisting or induced anti-AAV antibodies and virus capsid proteins has mainly been investigated by mutation analysis, by peptide insertions or by peptide scanning and several approaches were tested to develop AAV variants that improve tropism and that escape humoral immune response. These strategies include directed evolution, structure-based approaches, the engineering of chimeric AAV vectors (for example Bennett et al, 2020) or by displaying peptides of the surface of AAV vectors (Borner et al, 2020). Other proposed strategies to avoid the negative impact of neutralizing antibodies include modifying the route of administration (Mimuro et al, 2013), the discovery of new serotypes and variants (Salganik et al, 2015), the reduction of immunogenicity by PEGylation or polymer technologies (Balakrishnan et al, 2019) or the use of capsid decoys intra- (Mingozzi et al, 2013) or extracorporeally (Bertin et al, 2020). Mechanisms of immunogenicity and their clinical impact were extensively reviewed by Monahan et al, 2021.

US 2013/0259885 Al relates to immunomodulation with peptides containing epitopes recognized by CD4+ natural killer T cells. This is taught to be suitable for increasing efficiency of gene therapy. WO 2005/023848 A2 discloses administration of peptides to patients for increasing efficiency of an adenoviral vector.

WO 2019/018439 Al relates to the removal of AAV-neutralizing antibodies from a subject by apheresis prior to administering recombinant AAV comprising a heterologous polynucleotide to the subject. Bertin et al, 2020, discloses a similar apheresis approach. Further along similar lines, WO 00/20041 A2 relates to methods of enhancing the effectiveness of therapeutic viral agents by extracorporeal removal of anti-AdV-antibodies with affinity columns based on AdV subunits (i.e. selective apheresis) .

However, each of these approaches have disadvantages on their own.

Neutralizing antibodies are not only problematic with respect to AAV-based gene therapy or vaccine vectors. To date, Adenovirus (AdV) serotype 5 (Ad5), as the prototypic adenoviral vector, was tested in more than 400 clinical trials. Remarkably, up to 80% of the population carries neutralizing antibodies against Ad5 which has a negative impact on transgene expression or on the efficacy of vaccines against pathogens or cancer.

Importantly, neutralizing antibodies have recently turned out to be problematic in a clinical trial with a vaccine against SARS-CoV-2 : Zhu (Zhu et al, 2020) concluded that pre-existing Ad5 antibodies might have hampered the immune response against the SARS-CoV-2 vaccine. It was further concluded that there was also a negative impact on the duration of the immune response elicited by the vaccine because of pre-existing neutralizing antibodies against the viral vaccine vector.

Neutralizing antibodies and epitopes against all types of AdV and other viral vectors for vaccination and gene therapy were previously described e.g. in Tian et al, 2018; Wang et al, 2019; Fausther-Bovendo et al, 2014; and Mok et al, 2020). As with AAV vectors, much effort was made to circumvent preexisting anti vector immunity by engineering and fine mapping of epitopes of adenoviral vectors (Roberts et al, 2006).

Since such strategies are cumbersome and expensive, new approaches are needed to address the problem of viral vector neutralization .

It is thus an object of the present invention to provide compounds and methods which inhibit viral vector neutralization. Thereby, efficiency of non-pathogenic viral vectors (such as used in vaccines or in gene therapy) is typically increased.

The present invention provides a compound comprising

- a biopolymer scaffold and at least - a first peptide n-mer of the general formula:

P ( - S - P ) _(n-1 ) and

- a second peptide n-mer of the general formula:

P ( - S - P )(n-1) .

Independently for each occurrence, P is a peptide with a sequence length of 6-13 amino acids, and S is a non-peptide spacer. Independently for each of the peptide n-mers, n is an integer of at least 1, preferably of at least 2, more preferably of at least 3, especially of at least 4. Each of the peptide n- mers is bound to the biopolymer scaffold, preferably via a linker each. Further, independently for each occurrence, P has an amino-acid sequence comprising a sequence fragment with a length of at least six, preferably at least seven, more preferably at least eight, especially at least 9 (or 10, 11, 12 or 13) amino acids of a capsid protein sequence of a (non- pathogenic) viral vector (such as AAV or AdV), in particular of an AdV hexon protein sequence, an AdV fiber protein sequence, an AdV penton protein sequence, an AdV Illa protein sequence, an AdV VI protein sequence, an AdV VIII protein sequence or an AdV IX protein sequence or of any one of the capsid protein sequences identified in Fig. 10 and Fig. 11 or of any one of the capsid protein sequences listed in Cearley et al., 2008. Optionally at most three, preferably at most two, most preferably at least one amino acid of the sequence fragment is independently substituted by any other amino acid.

Preferably, at least one occurrence of P is P _a and/or at least one occurrence of P is P _b . P _a is a defined peptide (i.e. a peptide of defined sequence) with a sequence length of 6-13 amino acids, preferably 7-11 amino acids, more preferably 7-9 amino acids. P _b is a defined peptide (i.e. a peptide of defined sequence) with a sequence length of 6-13 amino acids, preferably 7-11 amino acids, more preferably 7-9 amino acids.

The present invention also provides a compound comprising

- a biopolymer scaffold and at least

- a first peptide n-mer which is a peptide dimer of the formula P _a — S — P _a or P _a — S — Pb, wherein P _a is a defined peptide (i.e. a peptide of defined sequence) with a sequence length of 6-13 amino acids, preferably 7-11 amino acids, more preferably 7-9 amino acids, P _b is a defined peptide (i.e. a peptide of defined sequence) with a sequence length of 6-13 amino acids, preferably 7-11 amino acids, more preferably 7-9 amino acids, and S is a non-peptide spacer, wherein the first peptide n-mer is bound to the biopolymer scaffold, preferably via a linker. P _a has an amino-acid sequence comprising a sequence fragment with a length of at least six, preferably at least seven, more preferably at least eight, especially at least 9 (or 10, 11, 12 or 13) amino acids of a capsid protein sequence of a (non-pathogenic) viral vector, in particular of an AdV hexon protein sequence, an AdV fiber protein sequence, an AdV penton protein sequence, an AdV Illa protein sequence, an AdV VI protein sequence, an AdV VIII protein sequence or an AdV IX protein sequence or of any one of the capsid protein sequences identified in Fig. 10 and Fig. 11 or of any one of the capsid protein sequences listed in Cearley et al., 2008. Optionally at most three, preferably at most two, most preferably at least one amino acid of the sequence fragment is independently substituted by any other amino acid.

This compound preferably comprises a second peptide n-mer which is a peptide dimer of the formula P _b — S — P _b or P _a — S — Pb, wherein the second peptide n-mer is bound to the biopolymer scaffold, preferably via a linker. P _b has an amino-acid sequence comprising a sequence fragment with a length of at least six, preferably at least seven, more preferably at least eight, especially at least 9 (or 10, 11, 12 or 13) amino acids of a capsid protein sequence of a (non-pathogenic) viral vector, in particular of an AdV hexon protein sequence, an AdV fiber protein sequence, an AdV penton protein sequence, an AdV Illa protein sequence, an AdV VI protein sequence, an AdV VIII protein sequence or an AdV IX protein sequence or of any one of the capsid protein sequences identified in Fig. 10 and Fig. 11 or of any one of the capsid protein sequences listed in Cearley et al., 2008. Optionally at most three, preferably at most two, most preferably at least one amino acid of the sequence fragment is independently substituted by any other amino acid.

Furthermore, the present invention provides a pharmaceutical composition comprising any one of the aforementioned compounds and at least one pharmaceutically acceptable excipient. Preferably, this pharmaceutical composition is for use in therapy, in particular in combination with a vaccination or gene therapy.

In another aspect, the present invention provides a method of sequestering (or depleting) one or more antibodies present in an individual, comprising obtaining a pharmaceutical composition as defined herein, the composition being non-immunogenic in the individual, where the one or more antibodies present in the individual are specific for at least one occurrence of P, or for peptide P _a and/or peptide P _b ,- and administering the pharmaceutical composition to the individual.

In yet another aspect, the present invention relates to a pharmaceutical composition (i.e. a vaccine or gene therapy composition), comprising the compound defined herein and further comprising the viral vector and optionally at least one pharmaceutically acceptable excipient. The viral vector typically comprises a peptide fragment with a sequence length of at least six, preferably at least seven, more preferably at least eight, especially at least 9 amino acids. The sequence of at least one occurrence of peptide P, or peptide P _a and/or peptide Pb, of the compound is at least 70% identical, preferably at least 75% identical, more preferably at least 80% identical, yet more preferably at least 85% identical, even more preferably at least 90% identical, yet even more preferably at least 95% identical, especially completely identical to the sequence of said peptide fragment. Preferably, this pharmaceutical composition is for use in vaccination or gene therapy and/or for use in prevention or inhibition of an undesirable immune reaction against the viral vector.

In even yet another aspect, the present invention provides a method of inhibiting a (undesirable) - especially humoral - immune reaction to a treatment with a vaccine or gene therapy composition in an individual in need of treatment with the vaccine or gene therapy composition or of inhibiting neutralization of a viral vector in a vaccine or gene therapy composition for an individual in need of treatment with the vaccine or gene therapy composition, comprising obtaining said vaccine or gene therapy composition; wherein the compound of the vaccine or gene therapy composition is non-immunogenic in the individual, and administering the vaccine or gene therapy composition to the individual.

In the course of the present invention, a compound was developed which is able to deplete (or sequester) antibodies against viral vectors in vivo and is therefore suitable to increase the efficiency of viral vectors.

Further, it was surprisingly found that the approach which is also used in the invention is particularly effective in reducing titres of undesired antibodies in an individual. In particular, the compound achieved especially good results with regard to selectivity, duration of titre reduction and/or level of titre reduction in an in vivo model (see experimental examples).

The detailed description given below relates to all of the above aspects of the invention unless explicitly excluded.

In general, antibodies are essential components of the humoral immune system, offering protection from infections by foreign organisms including bacteria, viruses, fungi or parasites. However, under certain circumstances - including autoimmune diseases, organ transplantation, blood transfusion or upon administration of biomolecular drugs or gene delivery vectors - antibodies can target the patient's own body (or the foreign tissue or cells or the biomolecular drug or vector just administered), thereby turning into harmful or disease-causing entities. Certain antibodies can also interfere with probes for diagnostic imaging. In the following, such antibodies are generally referred to as "undesired antibodies" or "undesirable antibodies".

With few exceptions, selective removal of undesired antibodies has not reached clinical practice. It is presently restricted to very few indications: One of the known techniques for selective antibody removal (although not widely established) is immunoapheresis. In contrast to immunoapheresis (which removes immunoglobulin), selective immunoapheresis involves the filtration of plasma through an extracorporeal, selective antibody-adsorber cartridge that will deplete the undesired antibody based on selective binding to its antigen binding site. Selective immunoapheresis has for instance been used for removing anti-A or anti-B antibodies from the blood prior to ABO-incompatible transplantation or with respect to indications in transfusion medicine (Teschner et al). Selective apheresis was also experimentally applied in other indications, such as neuroimmunological indications (Tetala et al) or myasthenia gravis (Lazaridis et al), but is not yet established in the clinical routine. One reason that selective immunoapheresis is only hesitantly applied is the fact that it is a cost intensive and cumbersome intervention procedure that requires specialized medical care. Moreover, it is not known in the prior art how to deplete undesired antibodies rapidly and efficiently.

Unrelated to apheresis, Morimoto et al. discloses dextran as a generally applicable multivalent scaffold for improving immunoglobulin-binding affinities of peptide and peptidomimetic ligands such as the FLAG peptide. WO 2011/130324 Al relates to compounds for prevention of cell injury. EP 3 059244 Al relates to a C-met protein agonist.

As mentioned, apheresis is applied extracorporeally. By contrast, also several approaches to deplete undesirable antibodies intracorporeally were proposed in the prior art, mostly in connection with certain autoimmune diseases involving autoantibodies or anti-drug antibodies:

Lorentz et al discloses a technique whereby erythrocytes are charged in situ with a tolerogenic payload driving the deletion of antigen-specific T cells. This is supposed to ultimately lead to reduction of the undesired humoral response against a model antigen. A similar approach is proposed in Pishesha et al. In this approach, erythrocytes are loaded ex vivo with a peptide- antigen construct that is covalently bound to the surface and reinjected into the animal model for general immunotolerance induction .

WO 92/13558 Al relates to conjugates of stable nonimmunogenic polymers and analogs of immunogens that possess the specific B cell binding ability of the immunogen and which, when introduced into individuals, induce humoral anergy to the immunogen. Accordingly, these conjugates are disclosed to be useful for treating antibody-mediated pathologies that are caused by foreign- or self-immunogens. In this connection, see also EP 0498 658 A2.

Taddeo et al discloses selectively depleting antibody producing plasma cells using anti-CD138 antibody derivatives fused to an ovalbumin model antigen thereby inducing receptor crosslinking and cell suicide in vitro selectively in those cells that express the antibody against the model antigen.

Apitope International NV (Belgium) is presently developing soluble tolerogenic T-cell epitope peptides which may lead to expression of low levels of co-stimulatory molecules from antigen presenting cells inducing tolerance, thereby suppressing antibody response (see e.g. Jansson et al). These products are currently under preclinical and early clinical evaluation, e.g. in multiple sclerosis, Grave's disease, intermediate uveitis, and other autoimmune conditions as well as Factor VIII intolerance.

Similarly, Selecta Biosciences, Inc. (USA) is currently pursuing strategies of tolerance induction by so-called Synthetic Vaccine Particles (SVPs). SVP-Rapamycin is supposed to induce tolerance by preventing undesired antibody production via selectively inducing regulatory T cells (see Mazor et al).

Mingozzi et al discloses decoy adeno-associated virus (AAV) capsids that adsorb antibodies but cannot enter a target cell.

WO 2015/136027 Al discloses carbohydrate ligands presenting the minimal Human Natural Killer-1 (HNK-1) epitope that bind to anti-MAG (myelin-associated glycoprotein) IgM antibodies, and their use in diagnosis as well as for the treatment of anti-MAG neuropathy. WO 2017/046172 Al discloses further carbohydrate ligands and moieties, respectively, mimicking glycoepitopes comprised by glycosphingolipids of the nervous system which are bound by anti-glycan antibodies associated with neurological diseases. The document further relates to the use of these carbohydrate ligands/moieties in diagnosis as well as for the treatment of neurological diseases associated with anti-glycan antibodies.

US 2004/0258683 Al discloses methods for treating systemic lupus erythematosus (SLE) including renal SLE and methods of reducing risk of renal flare in individuals with SLE, and methods of monitoring such treatment. One disclosed method of treating SLE including renal SLE and reducing risk of renal flare in an individual with SLE involves the administration of an effective amount of an agent for reducing the level of anti- double-stranded DNA (dsDNA) antibody, such as a dsDNA epitope as in the form of an epitope-presenting carrier or an epitopepresenting valency platform molecule, to the individual.

US patent no. 5,637,454 relates to assays and treatments of autoimmune diseases. Agents used for treatment might include peptides homologous to the identified antigenic, molecular mimicry sequences. It is disclosed that these peptides could be delivered to a patient in order to decrease the amount of circulating antibody with a particular specificity.

US 2007/0026396 Al relates to peptides directed against antibodies, which cause cold-intolerance, and the use thereof. It is taught that by using the disclosed peptides, in vivo or ex vivo neutralization of undesired autoantibodies is possible. A comparable approach is disclosed in WO 1992/014150 Al or in WO 1998/030586 A2.

WO 2018/102668 Al discloses a fusion protein for selective degradation of disease-causing or otherwise undesired antibodies. The fusion protein (termed "Seldeg") includes a targeting component that specifically binds to a cell surface receptor or other cell surface molecule at near-neutral pH, and an antigen component fused directly or indirectly to the targeting component. Also disclosed is a method of depleting a target antigen-specific antibody from a patient by administering to the patient a Seldeg having an antigen component configured to specifically bind the target antigen-specific antibody.

WO 2015/181393 Al concerns peptides grafted into sunflower- trypsin-inhibitor- (SFTI-) and cyclotide-based scaffolds. These peptides are disclosed to be effective in autoimmune disease, for instance citrullinated fibrinogen sequences that are grafted into the SFTI scaffold have been shown to block autoantibodies in rheumatoid arthritis and inhibit inflammation and pain. These scaffolds are disclosed to be non-immunogenic.

Erlandsson et al discloses in vivo clearing of idiotypic antibodies with anti-idiotypic antibodies and their derivatives. Berlin Cures Holding AG (Germany) has proposed an intravenous broad spectrum neutralizer DNA aptamer (see e.g. WO 2016/020377 Al and WO 2012/000889 Al) for the treatment of dilated cardiomyopathy and other GPCR-autoantibody related diseases that in high dosage is supposed to block autoantibodies by competitive binding to the antigen binding regions of autoantibodies. In general, aptamers did not yet achieve a breakthrough and are still in a preliminary stage of clinical development. The major concerns are still biostability and bioavailability, constraints such as nuclease sensitivity, toxicity, small size and renal clearance. A particular problem with respect to their use as selective antibody antagonists are their propensity to stimulate the innate immune response.

WO 00/33887 A2 discloses methods for reducing circulating levels of antibodies, particularly disease-associated antibodies. The methods entail administering effective amounts of epitope-presenting carriers to an individual. In addition, ex vivo methods for reducing circulating levels of antibodies are disclosed which employ epitope-presenting carriers.

US 6,022,544 A relates to a method for reducing an undesired antibody response in a mammal by administering to the mammal a non-immunogenic construct which is free of high molecular weight immunostimulatory molecules. The construct is disclosed to contain at least two copies of a B cell membrane immunoglobulin receptor epitope bound to a pharmaceutically acceptable non- immunogenic carrier.

However, the approaches to deplete undesirable antibodies intracorporeally disclosed in the prior art have many shortcomings. In particular, neither of them has been approved for regular clinical use.

The biopolymer scaffold used in the present invention may be a mammalian biopolymer such as a human biopolymer, a non-human primate biopolymer, a sheep biopolymer, a pig biopolymer, a dog biopolymer or a rodent biopolymer. In particular the biopolymer scaffold is a protein, especially a (non-modifled or nonmodified with respect to its amino-acid sequence) plasma protein. Preferably, the biopolymer scaffold is a mammalian protein such as a human protein, a non-human primate protein, a sheep protein, a pig protein, a dog protein or a rodent protein. Typically, the biopolymer scaffold is a non-immunogenic and/or non-toxic protein that preferably circulates in the plasma of healthy (human) individuals and can e.g. be efficiently scavenged or recycled by scavenging receptors, such as e.g. present on myeloid cells or on liver sinusoidal endothelial cells (reviewed by Sorensen et al 2015).

According to a particular preference, the biopolymer scaffold is a (preferably human) globulin, preferably selected from the group consisting of immunoglobulins, alphal-globulins, alpha2-globulins and beta-globulins, in particular immunoglobulin G, haptoglobin and transferrin. Haptoglobin in particular has several advantageous properties, as shown in Examples 5-9, especially an advantageous safety profile.

The biopolymer scaffold may also be (preferably human) albumin, hemopexin, alpha-l-antitrypsin, Cl esterase inhibitor, lactoferrin or non-immunogenic (i.e. non-immunogenic in the individual to be treated) fragments of all of the aforementioned proteins, including the globulins.

In another preference, the biopolymer scaffold is an anti- CD163 antibody (i.e. an antibody specific for a CD163 protein) or GDI63-binding fragment thereof.

Human CD163 (Cluster of Differentiation 163) is a 130 kDa membrane glycoprotein (formerly called M130) and prototypic class I scavenger receptor with an extracellular portion consisting of nine scavenger receptor cysteine-rich (SRCR) domains that are responsible for ligand binding. CD163 is an endocytic receptor present on macrophages and monocytes, it removes hemoglobin/haptoglobin complexes from the blood but it also plays a role in anti-inflammatory processes and wound healing. Highest expression levels of CD163 are found on tissue macrophages (e.g. Kupffer cells in the liver) and on certain macrophages in spleen and bone marrow. Because of its tissue- and cell-specific expression and entirely unrelated to depletion of undesirable antibodies, CD163 is regarded as a macrophage target for drug delivery of e.g. immunotoxins, liposomes or other therapeutic compound classes (Skytthe et al., 2020). Monoclonal anti-CD163 antibodies and the SRCR domains they are binding are for instance disclosed in Madsen et al., 2004, in particular Fig. 7. Further anti-CD163 antibodies and fragments thereof are e.g. disclosed in WO 2002/032941 A2 or WO 2011/039510 A2. At least two structurally different binding sites for ligands were mapped by using domain-specific antibodies such as e.g. monoclonal antibody (mAb) EDhul (see Madsen et al, 2004). This antibody binds to the third SRCR of CD163 and competes with hemoglobin/haptoglobin binding to CD163. Numerous other antibodies against different domains of CD163 were previously described in the literature, including Mac2-158, KiM8, GHI/61 and RM3/1, targeting SRCR domains 1, 3, 7 and 9, respectively. In addition, conserved bacterial binding sites were mapped and it was demonstrated that certain antibodies were able to inhibit either bacterial binding but not hemoglobin/haptoglobin complex binding and vice versa. This points to different modes of binding and ligand interactions of CD163 (Fabriek et al, 2009; see also citations therein).

Entirely unrelated to depletion of undesirable antibodies, CD163 was proposed as a target for cell-specific drug delivery because of its physiological properties. Tumor-associated macrophages represent one of the main targets where the potential benefit of GDI63-targeting is currently explored. Remarkably, numerous tumors and malignancies were shown to correlate with CD163 expression levels, supporting the use of this target for tumor therapy. Other proposed applications include CD163 targeting by anti-drug conjugates (ADCs) in chronic inflammation and neuroinflammation (reviewed in Skytthe et al., 2020). Therefore, CD163-targeting by ADCs notably with dexamethasone or stealth liposome conjugates represents therapeutic principle which is currently studied (Graversen et al., 2012; Etzerodt et al., 2012).

In that context, there are references indicating that anti- CD163 antibodies can be rapidly internalized by endocytosis when applied in vivo. This was shown for example for monoclonal antibody (mAb) Ed-2 (Dijkstra et al., 1985; Graversen et al., 2012) or for mAb Mac2-158 / KN2/NRY (Granfeldt et al., 2013). Based on those observations in combination with observations made in the course of the present invention (see in particular example section), anti-CD163 antibodies and GDI63-binding turned out to be highly suitable biopolymer scaffolds for depletion/sequestration of undesirable antibodies.

Numerous anti-CD163 antibodies and GDI63-binding fragments thereof are known in the art (see e.g. above). These are suitable to be used as a biopolymer scaffold for the present invention. For instance, any anti-CD163 antibody or fragment thereof mentioned herein or in WO 2011/039510 A2 (which is included herein by reference) may be used as a biopolymer scaffold in the invention. Preferably, the biopolymer scaffold of the inventive compound is antibody Mac2-48, Mac2-158, 5C6- FAT, BerMac3, or E10B10 as disclosed in WO 2011/039510, in particular humanised Mac2-48 or Mac2-158 as disclosed in WO 2011/039510 A2.

In a preferred embodiment, the anti-CD163 antibody or CD163- binding fragment thereof comprises a heavy-chain variable (V _H ) region comprising one or more complementarity-determining region (CDR) sequences selected from the group consisting of SEQ ID NOs: 11-13 of WO 2011/039510 A2.

In addition, or alternatively thereto, in a preferred embodiment, the anti-CD163 antibody or GDI63-binding fragment thereof comprises a light-chain variable (V _L ) region comprising one or more CDR sequences selected from the group consisting of SEQ ID NOs: 14-16 of WO 2011/039510 A2 or selected from the group consisting of SEQ ID NOs:17-19 of WO 2011/039510 A2.

In a further preferred embodiment, the anti-CD163 antibody or GDI63-binding fragment thereof comprises a heavy-chain variable (V _H ) region comprising or consisting of the amino acid sequence of SEQ ID NO: 20 of WO 2011/039510 A2.

In addition, or alternatively thereto, in a preferred embodiment, the anti-CD163 antibody or GDI63-binding fragment thereof comprises a light-chain variable (V _L ) region comprising or consisting of the amino acid sequence of SEQ ID NO: 21 of WO 2011/039510 A2.

In a further preferred embodiment, the anti-CD163 antibody or GDI63-binding fragment thereof comprises a heavy-chain variable (V _H ) region comprising or consisting of the amino acid sequence of SEQ ID NO: 22 of WO 2011/039510 A2. In addition, or alternatively thereto, in a preferred embodiment, the anti-CD163 antibody or GDI63-binding fragment thereof comprises a light-chain variable (V _L ) region comprising or consisting of the amino acid sequence of SEQ ID NO: 23 of WO 2011/039510 A2.

In a further preferred embodiment, the anti-CD163 antibody or GDI63-binding fragment thereof comprises a heavy-chain variable (V _H ) region comprising or consisting of the amino acid sequence of SEQ ID NO: 24 of WO 2011/039510 A2.

In addition, or alternatively thereto, in a preferred embodiment, the anti-CD163 antibody or GDI63-binding fragment thereof comprises a light-chain variable (V _L ) region comprising or consisting of the amino acid sequence of SEQ ID NO: 25 of WO 2011/039510 A2.

In the context of the present invention, the anti-CD163 antibody may be a mammalian antibody such as a humanized or human antibody, a non-human primate antibody, a sheep antibody, a pig antibody, a dog antibody or a rodent antibody. In embodiments, the anti-CD163 antibody may monoclonal.

According to a preference, the anti-CD163 antibody is selected from IgG, IgA, IgD, IgE and IgM.

According to a further preference, the GDI63-binding fragment is selected from a Fab, a Fab', a F(ab)2, a Fv, a single-chain antibody, a nanobody and an antigen-binding domain.

CD163 amino acid sequences are for instance disclosed in WO 2011/039510 A2 (which is included here by reference). In the context of the present invention, the anti-CD163 antibody or GDI63-binding fragment thereof is preferably specific for a human CD163, especially with the amino acid sequence of any one of SEQ ID NOs: 28-31 of WO 2011/039510 A2.

In a further preferred embodiment, the anti-CD163 antibody or GDI63-binding fragment thereof is specific for the extracellular region of CD163 (e.g. for human CD163: amino acids 42-1050 of UniProt Q86VB7, sequence version 2), preferably for an SRCR domain of CD163, more preferably for any one of SRCR domains 1-9 of CD163 (e.g. for human CD163: amino acids 51-152, 159-259, 266-366, 373-473, 478-578, 583-683, 719-819, 824-926 and 929-1029, respectively, of UniProt Q86VB7, sequence version 2), even more preferably for any one of SRCR domains 1-3 of CD163 (e.g. for human CD163: amino acids 51-152, 159-259, 266- 366, and 373-473, respectively, of UniProt Q86VB7, sequence version 2), especially for SRCR domain 1 of CD163 (in particular with the amino acid sequence of any one of SEQ ID NOs: 1-8 of WO 2011/039510 A2, especially SEQ ID NO: 1 of WO 2011/039510 A2).

In a particular preference, the anti-CD163 antibody or GDI63-binding fragment thereof is capable of competing for binding to (preferably human) CD163 with a (preferably human) hemoglobin-haptoglobin complex (e.g. in an ELISA).

In another particular preference, the anti-CD163 antibody or GDI63-binding fragment thereof is capable of competing for binding to human CD163 with any of the anti-human CD163 mAbs disclosed herein, in particular Mac2-48 or Mac2-158 as disclosed in WO 2011/039510 A2.

In yet another particular preference, the anti-CD163 antibody or GDI63-binding fragment thereof is capable of competing for binding to human CD163 with an antibody having a heavy chain variable (VH) region consisting of the amino acid sequence and having a light-chain variable (VL) region consisting of the amino acid sequence ID NO: 2) (e.g. in an ELISA).

Details on competitive binding experiments are known to the person of skilled in the art (e.g. based on ELISA) and are for instance disclosed in WO 2011/039510 A2 (which is included herein by reference).

The epitopes of antibodies E10B10 and Mac2-158 as disclosed in WO 2011/039510 were mapped (see example section). These epitopes are particularly suitable for binding of the anti-CD163 antibody (or GDI63-binding fragment thereof) of the inventive compound. Accordingly, in particularly preferred embodiment, the anti- CD163 antibody or GDI63-binding fragment thereof is specific for peptide consisting of 7-25, preferably 8-20, even more preferably 9-15, especially 10-13 amino acids, wherein the peptide comprises the amino acid sequence CSGRVEVKVQEEWGTVCNNGWSMEA (SEQ ID NO: 3) or a 7-24 amino-acid fragment thereof. Preferably, this peptide comprises the amino acid sequence GRVEVKVQEEW (SEQ ID NO: 4), WGTVCNNGWS (SEQ ID NO: 5) or WGTVCNNGW (SEQ ID NO: 6). More preferably, the peptide comprises an amino acid sequence selected from EWGTVCNNGWSME (SEQ ID NO: 7), QEEWGTVCNNGWS (SEQ ID NO: 8), WGTVCNNGWSMEA (SEQ ID NO: 9), EEWGTVCNNGWSM (SEQ ID NO: 10), VQEEWGTVCNNGW (SEQ ID NO: 11), EWGTVCNNGW (SEQ ID NO: 12) and WGTVCNNGWS (SEQ ID NO: 5). Even more preferably, the peptide consists of an amino acid sequence selected from EWGTVCNNGWSME (SEQ ID NO: 7), QEEWGTVCNNGWS (SEQ ID NO: 8), WGTVCNNGWSMEA (SEQ ID NO: 9), EEWGTVCNNGWSM (SEQ ID NO:10), VQEEWGTVCNNGW (SEQ ID NO: 11), EWGTVCNNGW (SEQ ID NO: 12) and WGTVCNNGWS (SEQ ID NO: 5), optionally with an N-terminal and/or C-terminal cysteine residue.

Accordingly, in another particularly preferred embodiment, the anti-CD163 antibody or GDI63-binding fragment thereof is specific for a peptide consisting of 7-25, preferably 8-20, even more preferably 9-15, especially 10-13 amino acids, wherein the peptide comprises the amino acid sequence DHVSCRGNESALWDCKHDGWG (SEQ ID NO: 13) or a 7-20 amino-acid fragment thereof. Preferably, this peptide comprises the amino acid sequence ESALW (SEQ ID NO: 14) or ALW. More preferably, the peptide comprises an amino acid sequence selected from ESALWDC (SEQ ID NO: 15), RGNESALWDC (SEQ ID NO: 16), SCRGNESALW (SEQ ID NO: 17), VSCRGNESALWDC (SEQ ID NO: 18), ALWDCKHDGW (SEQ ID NO: 19), DHVSCRGNESALW (SEQ ID NO: 20), CRGNESALWD (SEQ ID NO: 21), NESALWDCKHDGW (SEQ ID NO: 22) and ESALWDCKHDGWG (SEQ ID NO: 23). Even more preferably, the peptide consists of an amino acid sequence selected from ESALWDC (SEQ ID NO: 15), RGNESALWDC (SEQ ID NO: 16), SCRGNESALW (SEQ ID NO: 17), VSCRGNESALWDC (SEQ ID NO: 18), ALWDCKHDGW (SEQ ID NO: 19), DHVSCRGNESALW (SEQ ID NO: 20), CRGNESALWD (SEQ ID NO: 21), NESALWDCKHDGW (SEQ ID NO: 22) and ESALWDCKHDGWG (SEQ ID NO: 23), optionally with an N-terminal and/or C-terminal cysteine residue.

Accordingly, in another particularly preferred embodiment, the anti-CD163 antibody or GDI63-binding fragment thereof is specific for a peptide consisting of 7-25, preferably 8-20, even more preferably 9-15, especially 10-13 amino acids, wherein the peptide comprises the amino acid sequence SSLGGTDKELRLVDGENKCS (SEQ ID NO: 24) or a 7-19 amino-acid fragment thereof. Preferably, this peptide comprises the amino acid sequence SSLGGTDKELR (SEQ ID NO: 25) or SSLGG (SEQ ID NO: 26). More preferably, the peptide comprises an amino acid sequence selected from SSLGGTDKELR (SEQ ID NO: 25), SSLGGTDKEL (SEQ ID NO: 27), SSLGGTDKE (SEQ ID NO: 28), SSLGGTDK (SEQ ID NO: 29), SSLGGTD (SEQ ID NO: 30), SSLGGT (SEQ ID NO: 31) and SSLGG (SEQ ID NO: 26). Even more preferably, the peptide consists of an amino acid sequence selected from SSLGGTDKELR (SEQ ID NO: 25), SSLGGTDKEL (SEQ ID NO: 27), SSLGGTDKE (SEQ ID NO: 28), SSLGGTDK (SEQ ID NO: 29), SSLGGTD (SEQ ID NO: 30), SSLGGT (SEQ ID NO: 31) and SSLGG (SEQ ID NO: 26), optionally with an N-terminal and/or C-terminal cysteine residue.

The peptides (or peptide n-mers) are preferably covalently conjugated (or covalently bound) to the biopolymer scaffold via a (non-immunogenic) linker known in the art such as for example amine-to-sulfhydryl linkers and bifunctional NHS-PEG-maleimide linkers or other linkers known in the art. Alternatively, the peptides (or peptide n-mers) can be bound to the epitope carrier scaffold e.g. by formation of a disulfide bond between the protein and the peptide (which is also referred to as "linker" herein), or using non-covalent assembly techniques, spontaneous isopeptide bond formation or unnatural amino acids for bio- orthogonal chemistry via genetic code expansion techniques (reviewed by Howarth et al 2018 and Lim et al 2016). Covalent and non-covalent bioconjugation strategies suitable for the present invention are also discussed e.g. in Sunasee et al, 2014.

The compound of the present invention may comprise e.g. at least two, preferably between 3 and 40 copies of one or several different peptides (which may be present in different forms of peptide n-mers as disclosed herein). The compound may comprise one type of epitopic peptide (in other words: antibody-binding peptide or paratope-binding peptide), however the diversity of epitopic peptides bound to one biopolymer scaffold molecule can be a mixture of e.g. up to 8 different epitopic peptides.

Typically, since the peptides present in the inventive compound specifically bind to selected undesired antibodies, their sequence is usually selected and optimized such that they provide specific binding in order to guarantee selectivity of undesired antibody depletion from the blood. For this purpose, the peptide sequence of the peptides typically corresponds to the entire epitope sequence or portions of the undesired antibody epitope. The peptides used in the present invention can be further optimized by exchanging one, two or up to four aminoacid positions, allowing e.g. for modulating the binding affinity to the undesired antibody that needs to be depleted. Such single or multiple amino-acid substitution strategies that can provide "mimotopes" with increased binding affinity and are known in the field and were previously developed using phage display strategies or peptide microarrays. In other words, the peptides used in the present invention do not have to be completely identical to the native epitope sequences of the undesired antibodies.

Typically, the peptides used in the compound of the present invention (e.g. peptide P or P _a or Pb) are composed of one or more of the 20 amino acids commonly present in mammalian proteins. In addition, the amino acid repertoire used in the peptides may be expanded to post-translationally modified amino acids e.g. affecting antigenicity of proteins such as post translational modifications, in particular oxidative post translational modifications (see e.g. Ryan 2014) or modifications to the peptide backbone (see e.g. Muller 2018), or to non-natural amino acids (see e.g. Meister et al 2018). These modifications may also be used in the peptides e.g. to adapt the binding interaction and specificity between the peptide and the variable region of an undesired antibody. In particular, epitopes (and therefore the peptides used in the compound of the present invention) can also contain citrulline as for example in autoimmune diseases. Furthermore, by introducing modifications into the peptide sequence the propensity of binding to an HLA molecule may be reduced, the stability and the physicochemical characteristics may be improved or the affinity to the undesired antibody may be increased.

In many cases, the undesired antibody that is to be depleted is oligo- or polyclonal (e.g. autoantibodies, ADAs or alloantibodies are typically poly- or oligoclonal), implying that undesired (polyclonal) antibody epitope covers a larger epitopic region of a target molecule. To adapt to this situation, the compound of the present invention may comprise a mixture of two or several epitopic peptides (in other words: antibody-binding peptides or paratope-binding peptides), thereby allowing to adapt to the polyclonality or oligoclonality of an undesired antibody.

Such poly-epitopic compounds of the present invention can effectively deplete undesired antibodies and are more often effective than mono-epitopic compounds in case the epitope of the undesired antibody extends to larger amino acid sequence stretches .

It is advantageous if the peptides used for the inventive compound are designed such that they will be specifically recognized by the variable region of the undesired antibodies to be depleted. The sequences of peptides used in the present invention may e.g. be selected by applying fine epitope mapping techniques (i.e. epitope walks, peptide deletion mapping, amino acid substitution scanning using peptide arrays such as described in Carter et al 2004, and Hansen et al 2013) on the undesired antibodies.

According to a preferred embodiment, the viral vector is an AdV vector or an AAV vector, preferably specific for a human host.

In another preference, the sequence fragment as used herein comprises an epitope or epitope part (e.g. at least six, especially at least seven or even at least eight amino acids) of an AdV capsid protein or of an AAV capsid protein (see e.g. Example 10), in particular wherein the AAV is one of AAV-8, AAV- 9, AAV-6, AAV-2 or AAV-5, or of one of the following viral proteins identified by their UniProt accession code: A9RAI0, B5SUY7, 041855, 056137, 056139, P03135, P04133, P04882, P08362, P10269, P12538, P69353, Q5Y9B2, Q5Y9B4, Q65311,

Q6JC40, Q6VGT5, Q8JQF8, Q8JQG0, Q98654, Q9WBP8, Q9YIJ1, or of an AdV hexon protein, an AdV fiber protein, an AdV penton protein, an AdV Illa protein, an AdV VI protein, an AdV

VIII protein or an AdV IX protein or of any one of the capsid proteins identified in Fig. 10 and Fig. 11 or of any one of the capsid proteins listed in Cearley et al., 2008.

Particularly suitable epitopes for depleting neutralizing antibodies (against AAV and AdV) were found in epitope screens and screens of human sera (see in particular Examples 14-21). Accordingly, in a preferment, the sequence fragment as used herein comprises a sequence of at least 4 or at least 5 or at least 6, preferably at least 7, more preferably at least 8, even more preferably at least 9, yet even more preferably at least 10 consecutive amino acids selected from: the group of AdV sequences ETGPPTVPFLTPPF (SEQ ID NO: 32), HDSKLSIATQGPL (SEQ ID NO: 33), LNLRLGQGPLFINSAHNLDINY (SEQ ID NO: 34), VDPMDEPTLLYVLFEVFDW (SEQ ID NO: 35), MKRARPSEDTFNPVYPYD (SEQ ID NO: 36), ISGTVQSAHLIIRFD (SEQ ID NO: 37), LGQGPLFINSAHNLDINYNKGLYLF (SEQ ID NO: 38), SYPFDAQNQLNLRLGQGPLFIN (SEQ ID NO: 39), GDTTPSAYSMSFSWDWSGHNYIN (SEQ ID NO: 40), VLLNNSFLDPEYWNFRN (SEQ ID NO: 41), HNYINEIFATSSYTFSYIA (SEQ ID NO: 42), DEAATALEINLEEEDDDNEDEVDEQAEQQKTH (SEQ ID NO: 43), INLEEEDDDNEDEVDEQAEQ (SEQ ID NO: 44), DNEDEVDEQAEQQKTHVF (SEQ ID NO: 45), EWDEAATALEINLEE (SEQ ID NO: 46), PKW LYSEDVDIETPDTHISYMP (SEQ ID NO: 47), YIPESYKDRMYSFFRNF (SEQ ID NO: 48), DSIGDRTRYFSMW (SEQ ID NO: 49), SYKDRMYSFFRNF (SEQ ID NO: 50), and FLVQMLANYNIGYQGFY (SEQ ID NO: 51), or the group of AAV sequences WQNRDVYLQGPIWAKIP (SEQ ID NO: 52), DNTYFGYSTPWGYFDFNRFHC (SEQ ID NO: 53), MANQAKNWLPGPCY (SEQ ID NO: 54), LPYVLGSAHQGCLPPFP (SEQ ID NO: 55), NGSQAVGRSSFYCLEYF (SEQ ID NO: 56), PLIDQYLYYL (SEQ ID NO: 57), EERFFPSNGILIF (SEQ ID NO: 58), ADGVGSSSGNWHC (SEQ ID NO: 59), SEQ ID NOs: 383-1891 (see Table 1) - preferably group III of Table 1, more preferably group II of Table 1, especially group I of Table 1 - and SEQ ID NOs: 1892-2063 (see Table 2) - preferably group I of Table 2 - and sequences of group II or III of Table 3 (in particular SEQ ID NOs: 2064-2103), more preferably sequences of group I of Table 3, or the group of sequences of Table 4, in particular the group of sequences identified by SEQ ID NOs: 2104-2190.

It is particularly preferred that P _a and/or P _b or, independently for each occurrence, P comprises a 6-amino-acid fragment, preferably a 7-amino-acid-fragment, more preferably a 8-amino-acid-fragment , even more preferably a 9-amino-acid fragment, yet even more preferably a 10-amino-acid fragment, especially an entire sequence selected from the group of sequences consisting of GPPTVPFLTP (SEQ ID NO: 60), ETGPPTVPFLTPP (SEQ ID NO: 61), TGPPTVPFLT (SEQ ID NO: 62), PTVPFLTPPF (SEQ ID NO: 63), HDSKLSIATQGPL (SEQ ID NO: 64), SIATQGP (SEQ ID NO: 65), NLRLGQGPLF (SEQ ID NO: 66), QGPLFINSAH (SEQ ID NO: 67), PLFINSAHNLD (SEQ ID NO: 68), LGQGPLF (SEQ ID NO: 69), LNLRLGQGPL (SEQ ID NO: 70), GQGPLFI (SEQ ID NO: 71), NLRLGQGPLFINS (SEQ ID NO: 72), LFINSAHNLDINY (SEQ ID NO: 73), FINSAHNLDI (SEQ ID NO: 74), LRLGQGPLFI (SEQ ID NO: 75),

GPLFINSAHN (SEQ ID NO: 76), DEPTLLYVLFEVF (SEQ ID NO: 77),

TLLYVLFEVF (SEQ ID NO: 78), DEPTLLYVLF (SEQ ID NO: 79),

TLLYVLFEVFDW (SEQ ID NO: 80), TLLYVLF (SEQ ID NO: 81),

MDEPTLLYVLFEV (SEQ ID NO: 82), EPTLLYVLFE (SEQ ID NO: 83),

DPMDEPTLLYVLF (SEQ ID NO: 84), LLYVLFEVFD (SEQ ID NO: 85),

YVLFEVFDW (SEQ ID NO: 86), PTLLYVLFEV (SEQ ID NO: 87), PTLLYVLFEVFDV (SEQ ID NO: 88), LYVLFEVFDV (SEQ ID NO: 89),

EPTLLYVLFEVFD (SEQ ID NO: 90), LYVLFEV (SEQ ID NO: 91),

PMDEPTLLYVLFE (SEQ ID NO: 92), LLYVLFE (SEQ ID NO: 93),

VDPMDEPTLLYVL (SEQ ID NO: 94), YVLFEVF (SEQ ID NO: 95), PTLLYVL

(SEQ ID NO: 96), MKRARPSEDTF (SEQ ID NO: 97), KRARPSEDTF (SEQ ID NO: 98), MKRARPSEDT (SEQ ID NO: 99), MKRARPSEDTFN (SEQ ID NO: 100), ARPSEDTFNP (SEQ ID NO: 101), RARPSEDTFN (SEQ ID NO: 102), RPSEDTF (SEQ ID NO: 103), MKRARPSEDTFNP (SEQ ID NO: 104),

RARPSEDTFNPVY (SEQ ID NO: 105), ARPSEDT (SEQ ID NO: 106),

EDTFNPVYPY (SEQ ID NO: 107), RPSEDTFNPVYPY (SEQ ID NO: 108), KRARPSEDTFNPV (SEQ ID NO: 109), DTFNPVY (SEQ ID NO: 110),

RPSEDTFNPV (SEQ ID NO: 111), PSEDTFNPVY (SEQ ID NO: 112),

DTFNPVYPYD (SEQ ID NO: 113), VQSAHLIIRF (SEQ ID NO: 114),

AHLIIRF (SEQ ID NO: 115), SGTVQSAHLIIRE (SEQ ID NO: 116), TVQSAHLIIR (SEQ ID NO: 117), HLIIRFD (SEQ ID NO: 118), SAHLIIR (SEQ ID NO: 119), QSAHLIIRFD (SEQ ID NO: 120), ISGTVQSAHLIIR

(SEQ ID NO: 121), GTVQSAHLII (SEQ ID NO: 122), GTVQSAHLIIRFD

(SEQ ID NO: 123), QSAHLII (SEQ ID NO: 124), HNLDINY (SEQ ID NO:

125), LFINSAHNLDINY (SEQ ID NO: 126), NLDINYNKGLYLF (SEQ ID NO: 127), FVSPNG (SEQ ID NO: 128), NYINEIF (SEQ ID NO: 129), NKGLYLF (SEQ ID NO: 130), INYNKGLYLF (SEQ ID NO: 131), NSAHNLDINY (SEQ ID NO: 132), WDWSGHNYINEIF (SEQ ID NO: 133), SGHNYINEIF (SEQ ID NO: 134), LGTGLSF (SEQ ID NO: 135), PFLTPPF (SEQ ID NO: 136), LGQGPLF (SEQ ID NO: 137), NLRLGQGPLF (SEQ ID NO: 138), NQLNLRLGQGPLF (SEQ ID NO: 139), GQGPLFI (SEQ ID NO: 140), QLNLRLGQGPLFI (SEQ ID NO: 141), SYPFDAQNQLNLR (SEQ ID NO: 142), YPFDAQNQLNLRL (SEQ ID NO: 143), LRLGQGPLFI (SEQ ID NO: 144), NQLNLRL (SEQ ID NO: 145), FDAQNQLNLR (SEQ ID NO: 146), QNQLNLR (SEQ ID NO: 147), QGPLFIN (SEQ ID NO: 148), PFDAQNQLNLRLG (SEQ ID NO: 149), DAQNQLNLRL (SEQ ID NO: 150), RLGQGPLFIN (SEQ ID NO: 151), QLNLRLG (SEQ ID NO: 152), FDAQNQLNLRLGQ (SEQ ID NO: 153), LNLRLGQGPLFIN (SEQ ID NO: 154), AQNQLNLRLG (SEQ ID NO: 155), AQNQLNL (SEQ ID NO: 156), LNLRLGQ (SEQ ID NO: 157), SYPFDAQNQL (SEQ ID NO: 158), PFDAQNQLNL (SEQ ID NO: 159), YSMSFSW (SEQ ID NO: 160), TPSAYSMSFSWDW (SEQ ID NO: 161), MSFSWDW (SEQ ID NO: 162), PSAYSMSFSW (SEQ ID NO: 163), DTTPSAYSMSFSW (SEQ ID NO: 164), TTPSAYSMSF (SEQ ID NO: 165), YSMSFSWDWS (SEQ ID NO: 166), TGDTTPSAYSMSF (SEQ ID NO: 167), FSWDWSGHNY (SEQ ID NO: 168), SFSWDWS (SEQ ID NO: 169), SAYSMSF (SEQ ID NO: 170), SFSWDWSGHN (SEQ ID NO: 171), SAYSMSFSWD (SEQ ID NO: 172), SMSFSWD (SEQ ID NO: 173), SWDWSGHNYI (SEQ ID NO: 174), AYSMSFS (SEQ ID NO: 175), SMSFSWDWSGHNY (SEQ ID NO: 176), FSWDWSG (SEQ ID NO: 177), SWDWSGH (SEQ ID NO: 178), FLDPEYWNFR (SEQ ID NO: 179), SFLDPEYWNF (SEQ ID NO: 180), PEYWNFR (SEQ ID NO: 181), LNNSFLDPEYWNF (SEQ ID NO: 182), NNSFLDPEYWNFR (SEQ ID NO: 183), FLDPEYW (SEQ ID NO: 184), DPEYWNF (SEQ ID NO: 185), NNSFLDPEYW (SEQ ID NO: 186), VLLNNSFLDPEYW (SEQ ID NO: 187), EYWNFRN (SEQ ID NO: 188), LNNSFLDPEY (SEQ ID NO: 189), LDPEYWNFRN (SEQ ID NO: 190), LNNSFLD (SEQ ID NO: 191), NSFLDPEYWN (SEQ ID NO: 192), SSYTFSY (SEQ ID NO: 193), FATSSYTFSY (SEQ ID NO: 194), YINEIFATSSYTF (SEQ ID NO: 195), SYTFSYI (SEQ ID NO: 196), ATSSYTF (SEQ ID NO: 197), EIFATSSYTF (SEQ ID NO: 198), NEIFATSSYTFSY (SEQ ID NO: 199), ATSSYTFSYI (SEQ ID NO: 200), HNYINEIFATSSY (SEQ ID NO: 201), IFATSSY (SEQ ID NO: 202), INEIFATSSY (SEQ ID NO: 203), NYINEIFATSSYT (SEQ ID NO: 204), YINEIFA (SEQ ID NO: 205), YTFSYIA (SEQ ID NO: 206), EIFATSSYTFSYI (SEQ ID NO: 207), ALEINLEEEDDDN (SEQ ID NO: 208), ATALEINLEEEDD (SEQ ID NO: 209), EAATALEINLEEE (SEQ ID NO: 210), LEINLEE (SEQ ID NO: 211), TALEINLEEEDDD (SEQ ID NO: 212), EINLEEE (SEQ ID NO: 213), ALEINLEEED (SEQ ID NO: 214), LEINLEEEDD (SEQ ID NO: 215), TALEINLEEE (SEQ ID NO: 216), DEAATALEINLEE (SEQ ID NO: 217), LEINLEEEDDDNE (SEQ ID NO: 218), AATALEINLEEED (SEQ ID NO: 219), EINLEEEDDD (SEQ ID NO: 220), ATALEINLEE (SEQ ID NO: 221), INLEEEDDDN (SEQ ID NO: 222), NLEEEDDDNE (SEQ ID NO: 223), DEVDEQA (SEQ ID NO: 224), EDDDNEDEVDEQA (SEQ ID NO: 225), DDNEDEVDEQAEQ (SEQ ID NO: 226), EVDEQAE (SEQ ID NO: 227), DNEDEVDEQA (SEQ ID NO: 228), VDEQAEQ (SEQ ID NO: 229), EDEVDEQAEQQKT (SEQ ID NO: 230), EDEVDEQAEQ

(SEQ ID NO: 231), DEVDEQAEQQKTH (SEQ ID NO: 232), NEDEVDEQAEQQK

(SEQ ID NO: 233), DEVDEQAEQQ (SEQ ID NO: 234), EINLEEEDDDNED

(SEQ ID NO: 235), NLEEEDDDNEDEV (SEQ ID NO: 236), INLEEED (SEQ

ID NO: 237), LEEEDDDNED (SEQ ID NO: 238), INLEEEDDDNEDE (SEQ ID NO: 239), DDDNEDEVDEQAE (SEQ ID NO: 240), LEEEDDDNEDEVD (SEQ ID NO: 241), DDNEDEVDEQ (SEQ ID NO: 242), EDDDNED (SEQ ID NO: 243), NLEEEDD (SEQ ID NO: 244), DDNEDEV (SEQ ID NO: 245), DDDNEDEVDE (SEQ ID NO: 246), DDDNEDE (SEQ ID NO: 247), EEEDDDNEDE (SEQ ID NO: 248), EEDDDNE (SEQ ID NO: 249), EDDDNEDEVD (SEQ ID NO: 250), EDEVDEQ (SEQ ID NO: 251), EEDDDNEDEVDEQ (SEQ ID NO: 252), EEDDDNEDEV (SEQ ID NO: 253), EEEDDDNEDEVDE (SEQ ID NO: 254),

EVDEQAEQQK (SEQ ID NO: 255), DNEDEVDEQAEQQ (SEQ ID NO: 256),

VDEQAEQQKT (SEQ ID NO: 257), EVDEQAEQQKTHV (SEQ ID NO: 258),

VDEQAEQQKTHVF (SEQ ID NO: 259), ALEINLE (SEQ ID NO: 260), WDEAATALEINLE (SEQ ID NO: 261), AATALEINLE (SEQ ID NO: 262),

EWDEAATALEINL (SEQ ID NO: 263), EAATALEINL (SEQ ID NO: 264),

LYSEDVDIET (SEQ ID NO: 265), LYSEDVDIETPDT (SEQ ID NO: 266),

KW LYSEDVDIET (SEQ ID NO: 267), IETPDTH (SEQ ID NO: 268), VDIETPDTHI (SEQ ID NO: 269), VLYSEDVDIE (SEQ ID NO: 270), DVDIETPDTHISY (SEQ ID NO: 271), W LYSEDVDIETP (SEQ ID NO: 272), SEDVDIETPDTHI (SEQ ID NO: 273), ETPDTHI (SEQ ID NO: 274), VLYSEDVDIETPD (SEQ ID NO: 275), DVDIETPDTH (SEQ ID NO: 276), DIETPDTHIS (SEQ ID NO: 277), EDVDIETPDTHIS (SEQ ID NO: 278), IETPDTHISY (SEQ ID NO: 279), YSEDVDIETPDTH (SEQ ID NO: 280), VDIETPDTHISYM (SEQ ID NO: 281), PKW LYSEDVDIE (SEQ ID NO: 282), DIETPDT (SEQ ID NO: 283), DIETPDTHISYMP (SEQ ID NO: 284), EDVDIETPDT (SEQ ID NO: 285), ETPDTHISYM (SEQ ID NO: 286), IETPDTHISYMP (SEQ ID NO: 287), DRMYSFFRNF (SEQ ID NO: 288), DRMYSFF (SEQ ID NO: 289), YSFFRNF (SEQ ID NO: 290), IPESYKDRMYSFF (SEQ ID NO: 291), SYKDRMYSFF (SEQ ID NO: 292), ESYKDRMYSF (SEQ ID NO: 293), KDRMYSF (SEQ ID NO: 294), YIPESYKDRMYSF (SEQ ID NO: 295), PESYKDRMYSFFR (SEQ ID NO: 296), YKDRMYSFFR (SEQ ID NO: 297), TRYFSMW (SEQ ID NO: 298), GDRTRYF (SEQ ID NO: 299), DSIGDRTRYF (SEQ ID NO: 300), DSIGDRTRYFSMW (SEQ ID NO: 301), GDRTRYFSMW (SEQ ID NO: 302), DRMYSFFRNF (SEQ ID NO: 303), SYKDRMYSFFRNF (SEQ ID NO: 304), NYNIGYQGFY (SEQ ID NO: 305), ANYNIGYQGF (SEQ ID NO: 306), MLANYNIGYQGFY (SEQ ID NO: 307), IGYQGFY (SEQ ID NO: 308), FLVQMLANYNIGY (SEQ ID NO: 309), NIGYQGF (SEQ ID NO: 310) and QMLANYNIGYQGF (SEQ ID NO: 311), optionally wherein at most three, preferably at most two, most preferably at least one amino acid is independently substituted by any other amino acid.

In another preferred embodiment, P _a and/or P _b or, independently for each occurrence, P comprises a 6-amino-acid fragment, preferably a 7-amino-acid-fragment, more preferably a 8-amino-acid-fragment, even more preferably a 9-amino-acid fragment, yet even more preferably a 10-amino-acid fragment or even a 11-amino-acid-fragment or yet even a 12-amino-acid- fragment, especially a 13-amino-acid-fragment selected from the group of sequences consisting of SEQ ID NOs: 383-1891 (see Table 1) - preferably group III of Table 1, more preferably group II of Table 1, especially group I of Table 1 - and SEQ ID NOs: 1892-2063 (see Table 2) - preferably group I of Table 2 - and sequences of group II or III of Table 3 (in particular SEQ ID NOs: 2064-2103), more preferably sequences of group I of Table 3, optionally wherein at most three, preferably at most two, most preferably at least one amino acid is independently substituted by any other amino acid.

In another preferred embodiment, P _a and/or P _b or, independently for each occurrence, P comprises a 6-amino-acid fragment, preferably a 7-amino-acid-fragment, more preferably a 8-amino-acid-fragment, even more preferably a 9-amino-acid fragment, yet even more preferably a 10-amino-acid fragment or even a 11-amino-acid-fragment or yet even a 12-amino-acid- fragment, especially a 13-amino-acid-fragment selected from the group of sequences of Table 4, in particular the group of sequences identified by SEQ ID NOs: 2104-2190, optionally wherein at most three, preferably at most two, most preferably at least one amino acid is independently substituted by any other amino acid.

It is further particularly preferred that P _a and/or P _b or, independently for each occurrence, P comprises a 6-amino-acid fragment, preferably a 7-amino-acid-fragment, more preferably a 8-amino-acid-fragment , even more preferably a 9-amino-acid fragment, yet even more preferably a 10-amino-acid fragment, especially an entire sequence selected from the group of sequences consisting of YLQGPIW (SEQ ID NO: 312), VYLQGPI (SEQ ID NO: 313), WQNRDVY (SEQ ID NO: 314), DVYLQGP (SEQ ID NO: 315), QNRDVYL (SEQ ID NO: 316), LQGPIWA (SEQ ID NO: 317), RDVYLQG (SEQ ID NO: 318), NRDVYLQ (SEQ ID NO: 319), YFGYSTPWGYFDF (SEQ ID NO: 320), FGYSTPWGYF (SEQ ID NO: 321), GYSTPWGYFD (SEQ ID NO: 322), YSTPWGYFDF (SEQ ID NO: 323), NTYFGYSTPWGYF (SEQ ID NO: 324), TPWGYFDFNRFHC (SEQ ID NO: 325), TYFGYSTPWGYFD (SEQ ID NO: 326), DNTYFGYSTPWGY (SEQ ID NO: 327), YFGYSTPWGY (SEQ ID NO: 328), FGYSTPWGYFDFN (SEQ ID NO: 329), NWLPGPC (SEQ ID NO: 330), WLPGPCY (SEQ ID NO: 331), QAKNWLPGPC (SEQ ID NO: 332), AKNWLPGPCY (SEQ ID NO: 333), MANQAKNWLPGPC (SEQ ID NO: 334), QGCLPPF (SEQ ID NO: 335), GCLPPFP (SEQ ID NO: 336), VLGSAHQGCLPPF (SEQ ID NO: 337), LPYVLGSAHQGCL (SEQ ID NO: 338), YVLGSAHQGC (SEQ ID NO: 339), CLPPFPA (SEQ ID NO: 340), SAHQGCLPPF (SEQ ID NO: 341), VLGSAHQGCL (SEQ ID NO: 342), PYVLGSAHQGCLP (SEQ ID NO: 343), GRSSFYC (SEQ ID NO: 344), AVGRSSFYCLEYF (SEQ ID NO: 345), AVGRSSFYCL (SEQ ID NO: 346), QAVGRSSFYCLEY (SEQ ID NO: 347), NGSQAVGRSSFYC (SEQ ID NO: 348), DQYLYYL (SEQ ID NO: 349), PLIDQYLYYL (SEQ ID NO: 350), IDQYLYY (SEQ ID NO: 351), FFPSNGILIF (SEQ ID NO: 352), EERFFPSNGILIF

(SEQ ID NO: 353), VGSSSGNWHC (SEQ ID NO: 354) and ADGVGSSSGNWHC

(SEQ ID NO: 355), optionally wherein at most three, preferably at most two, most preferably at least one amino acid is independently substituted by any other amino acid.

According to a further preference, P _a and/or P _b or, independently for each occurrence, P consists of a 6-amino-acid fragment, preferably a 7-amino-acid-fragment, more preferably a 8-amino-acid-fragment, even more preferably a 9-amino-acid fragment, yet even more preferably a 10-amino-acid fragment, especially an entire sequence selected from the group of sequences set forth in either of the four paragraphs right above, optionally wherein at most three, preferably at most two, most preferably at least one amino acid is independently substituted by any other amino acid, optionally with an N- terminal and/or C-terminal cysteine residue.

In the entire context of the present invention, if a peptide, e.g. P _a and/or P _b or (independently for each occurrence) peptide P, contains a fragment of at least 4 consecutive amino acids selected from a sequence listed in a row of any one of Tables 1-4 (see below in the Examples section), it is preferred that this fragment is extended (N-terminally or C-terminally) such that the peptide actually contains a longer fragment (e.g. at least 6 or at least 7 or at least 8 or at least 9 or at least

10 or at least 11 or at least 12 or 13 amino acids long) of the source protein given in the same row of the table. In other words, it is preferred that the peptide contains a portion of at least 5 or at least 6 or at least 7 or at least 8 or at least 9 or at least 10 or at least 11 or at least 12 or 13 consecutive amino acids of the viral source protein of the fragment sequence (as given in Tables 1-4).

It is highly preferred that the peptides used for the inventive compound do not bind to any HLA Class I or HLA Class

11 molecule (i.e. of the individual to be treated, e.g. human), in order to prevent presentation and stimulation via a T-cell receptor in vivo and thereby induce an immune reaction. It is generally not desired to involve any suppressive (or stimulatory) T-cell reaction in contrast to antigen-specific immunologic tolerization approaches. Therefore, to avoid T-cell epitope activity as much as possible, the peptides of the compound of the present invention (e.g. peptide P or P _a or Pb) preferably fulfil one or more of the following characteristics:

- To reduce the probability for a peptide used in the compound of the present invention to bind to an HLA Class II or Class I molecule, the peptide (e.g. peptide P or P _a or P _b ) has a preferred length of 4-8 amino acids, although somewhat shorter or longer lengths are still acceptable.

- To further reduce the probability that such a peptide binds to an HLA Class II or Class I molecule, it is preferred to test the candidate peptide sequence by HLA binding prediction algorithms such as NetMHCII-2.3 (reviewed by Jensen et al 2018). Preferably, a peptide (e.g. peptide P or P _a or Pb) used in the compound of the present invention has (predicted) HLA binding (IC50) of at least 500 nM. More preferably, HLA binding (IC50) is more than 1000 nM, especially more than 2000 nM (cf. e.g. Peters et al 2006). In order to decrease the likelihood of HLA Class I binding, NetMHCpan 4.0 may also be applied for prediction (Jurtz et al 2017).

- To further reduce the probability that such a peptide binds to an HLA Class I molecule, the NetMHCpan Rank percentile threshhold can be set to a background level of 10% according to Ko§aloglu-Yalgin et al, 2018. Preferably, a peptide (e.g. peptide P or P _a or Pb) used in the compound of the present invention therefore has a %Rank value of more than 3, preferably more than 5, more preferably more than 10 according to the NetMHCpan algorithm.

- To further reduce the probability that such a peptide binds to an HLA Class II molecule, it is beneficial to perform in vitro HLA-binding assays commonly used in the art such as for example refolding assays, iTopia, peptide rescuing assays or array-based peptide binding assays. Alternatively, or in addition thereto, LC-MS based analytics can be used, as e.g. reviewed by Gfeller et al 2016.

For stronger reduction of the titre of the undesired antibodies, it is preferred that the peptides used in the present invention are circularized (see also Example 4). Accordingly, in a preferred embodiment, at least one occurrence of P is a circularized peptide. Preferably at least 10% of all occurrences of P are circularized peptides, more preferably at least 25% of all occurrences of P are circularized peptides, yet more preferably at least 50% of all occurrences of P are circularized peptides, even more preferably at least 75% of all occurrences of P are circularized peptides, yet even more preferably at least 90% of all occurrences of P are circularized peptides or even at least 95% of all occurrences of P are circularized peptides, especially all of the occurrences of P are circularized peptides. Several common techniques are available for circularization of peptides, see e.g. Ong et al 2017. It goes without saying that "circularized peptide" as used herein shall be understood as the peptide itself being circularized, as e.g. disclosed in Ong et al. (and not e.g. grafted on a circular scaffold with a sequence length that is longer than 13 amino acids). Such peptides may also be referred to as cyclopeptides herein.

Further, for stronger reduction of the titre of the undesired antibodies relative to the amount of scaffold used, in a preferred embodiment of the compound of the present invention, independently for each of the peptide n-mers, n is at least 2, more preferably at least 3, especially at least 4. Usually, in order to avoid complexities in the manufacturing process, independently for each of the peptide n-mers, n is less than 10, preferably less than 9, more preferably less than 8, even more preferably less than 7, yet even more preferably less than 6, especially less than 5. To benefit from higher avidity through divalent binding of the undesired antibody, it is highly preferred that, for each of the peptide n-mers, n is 2.

For multivalent binding of the undesired antibodies, it is advantageous that the peptide dimers or n-mers are spaced by a hydrophilic, structurally flexible, immunologically inert, nontoxic and clinically approved spacer such as (hetero- )bifunctional and -trifunctional Polyethylene glycol (PEG) spacers (e.g. NHS-PEG-Maleimide) - a wide range of PEG chains is available and PEG is approved by the FDA. Alternatives to PEG linkers such as immunologically inert and non-toxic synthetic polymers or glycans are also suitable. Accordingly, in the context of the present invention, the spacer (e.g. spacer S) is preferably selected from PEG molecules or glycans. For instance, the spacer such as PEG can be introduced during peptide synthesis. Such spacers (e.g. PEG spacers) may have a molecular weight of e.g. 10000 Dalton. Evidently, within the context of the present invention, the covalent binding of the peptide n- mers to the biopolymer scaffold via a linker each may for example also be achieved by binding of the linker directly to a spacer of the peptide n-mer (instead of, e.g., to a peptide of the peptide n-mer).

Preferably, each of the peptide n-mers is covalently bound to the biopolymer scaffold, preferably via a linker each.

As used herein, the linker may e.g. be selected from disulphide bridges and PEG molecules.

According to a further preferred embodiment of the inventive compound, independently for each occurrence, P is P _a or P _b .

Furthermore, it is preferred when in the first peptide n- mer, each occurrence of P is P _a and, in the second peptide n-mer, each occurrence of P is P _b . Alternatively, or in addition thereto, P _a and/or P _b is circularized.

Divalent binding is particularly suitable to reduce antibody titres. According, in a preferred embodiment, the first peptide n-mer is P _a - S - P _a and the second peptide n-mer is P _a - S - P _a ; the first peptide n-mer is P _a - S - P _a and the second peptide n-mer is P _b - S - P _b ; the first peptide n-mer is P _b - S - P _b and the second peptide n-mer is P _b - S - P _b ," the first peptide n-mer is P _a - S - P _b and the second peptide n-mer is P _a - S - P _b ," the first peptide n-mer is P _a - S - P _b and the second peptide n-mer is P _a - S - P _a ; or the first peptide n-mer is P _a - S - P _b and the second peptide n-mer is P _b - S - P _b .

For increasing effectivity, in a preferred embodiment the first peptide n-mer is different from the second peptide n-mer. For similar reasons, preferably, the peptide P _a is different from the peptide Pb, preferably wherein the peptide P _a and the peptide P _b are two different epitopes of the same antigen or two different epitope parts of the same epitope.

Especially for better targeting of polyclonal antibodies, it is advantageous when the peptide P _a and the peptide P _b comprise the same amino-acid sequence fragment, wherein the amino-acid sequence fragment has a length of at least 2 amino acids, preferably at least 3 amino acids, more preferably at least 4 amino acids, yet more preferably at least 5 amino acids, even more preferably at least 6 amino acids, yet even more preferably at least 7 amino acids, especially at least 8 amino acids or even at least 9 amino acids.

Further, for stronger reduction of the titre of the undesired antibodies relative to the amount of scaffold used, the compound comprises a plurality of said first peptide n-mer (e.g. up to 10 or 20 or 30) and/or a plurality of said second peptide n-mer (e.g. up to 10 or 20 or 30).

As also illustrated above, it is highly preferred when the compound of the present invention is non-immunogenic in a mammal, preferably in a human, in a non-human primate, in a sheep, in a pig, in a dog or in a rodent.

In the context of the present invention, a non-immunogenic compound preferably is a compound wherein the biopolymer scaffold (if it is a protein) and/or the peptides (of the peptide n-mers) have an IC50 higher than 100 nM, preferably higher than 500 nM, even more preferably higher than 1000 nM, especially higher than 2000 nM, against HLA-DRBl_0101 as predicted by the NetMHCII-2.3 algorithm. The NetMHCII-2.3 algorithm is described in detail in Jensen et al, which is incorporated herein by reference. The algorithm is publicly available under http://www.cbs.dtu.dk/services/NetMHCI1-2.3/. Even more preferably, a non-immunogenic compound (or pharmaceutical composition) does not bind to any HLA and/or MHC molecule (e.g. in a mammal, preferably in a human, in a non- human primate, in a sheep, in a pig, in a dog or in a rodent; or of the individual to be treated) in vivo.

According to a further preference, the compound is for intracorporeal sequestration (or intracorporeal depletion) of at least one antibody (against the viral vector or neutralizing the viral vector) in an individual, preferably in the bloodstream of the individual and/or for reduction of the titre of at least one antibody (against the viral vector or neutralizing the viral vector) in the individual, preferably in the bloodstream of the individual . In another preferred embodiment, the entire sequence, optionally with the exception of an N-terminal and/or C-terminal cysteine, of at least one occurrence of P, preferably of at least 10% of all occurrences of P, more preferably of at least 25% of all occurrences of P, yet more preferably of at least 50% of all occurrences of P, even more preferably of at least 75% of all occurrences of P, yet even more preferably of at least 90% of all occurrences of P or even of at least 95% of all occurrences of P, especially of all of the occurrences of P, is identical to a sequence fragment of a protein, wherein the protein is identified by one of the UniProt accession codes disclosed herein; optionally wherein the sequence fragment comprises at most five, preferably at most four, more preferably at most three, even more preferably at most two, especially at most one amino acid substitutions (e.g. for the purposes mentioned above, such as creating mimotopes).

In another preferred embodiment, the entire sequence, optionally with the exception of an N-terminal and/or C-terminal cysteine, of peptide P _a is identical to a sequence fragment of a protein, wherein the protein is identified by one of the UniProt accession codes disclosed herein; optionally wherein said sequence fragment comprises at most five, preferably at most four, more preferably at most three, even more preferably at most two, especially at most one amino acid substitutions (e.g. for the purposes mentioned above, such as creating mimotopes).

In another preferred embodiment, the entire sequence, optionally with the exception of an N-terminal and/or C-terminal cysteine, of peptide P _b is identical to a sequence fragment of a protein, wherein the protein is identified by one of the UniProt accession codes disclosed herein; optionally wherein said sequence fragment comprises at most five, preferably at most four, more preferably at most three, even more preferably at most two, especially at most one amino acid substitutions (e.g. for the purposes mentioned above, such as creating mimotopes).

In another preferred embodiment, the entire sequence, optionally with the exception of an N-terminal and/or C-terminal cysteine, of peptide P _a is identical to a sequence fragment of a protein and the entire sequence, optionally with the exception of an N-terminal and/or C-terminal cysteine, of peptide P _b is identical to the same or another, preferably another, sequence fragment of the same protein, wherein the protein is identified by one of the UniProt accession codes listed herein; optionally wherein said sequence fragment and/or said another sequence fragment comprises at most five, preferably at most four, more preferably at most three, even more preferably at most two, especially at most one amino acid substitutions (e.g. for the purposes mentioned above, such as creating mimotopes).

In an aspect, the present invention relates to a pharmaceutical composition comprising the inventive and at least one pharmaceutically acceptable excipient.

In embodiments, the composition is prepared for intraperitoneal, subcutaneous, intramuscular and/or intravenous administration. In particular, the composition is for repeated administration (since it is typically non-immunogenic).

In a preference, the molar ratio of peptide P or P _a or P _b to biopolymer scaffold in the composition is from 2:1 to 100:1, preferably from 3:1 to 90:1, more preferably from 4:1 to 80:1, even more preferably from 5:1 to 70:1, yet even more preferably from 6:1 to 60:1, especially from 7:1 to 50:1 or even from 8:10 to 40:1.

In another aspect, the compound of the present invention is for use in therapy.

In the course of the present invention, it turned out that the in vivo kinetics of undesirable-antibody lowering by the inventive compound is typically very fast, sometimes followed by a mild rebound of the undesirable antibody. It is thus particularly preferred when the compound (or the pharmaceutical composition comprising the compound) is administered at least twice within a 96-hour window, preferably within a 72-hour window, more preferably within a 48-hour window, even more preferably within a 36-hour window, yet even more preferably within a 24-hour window, especially within a 18-hour window or even within a 12-hour window; in particular wherein this window is followed by administration of the vaccine or gene therapy composition as described herein within 24 hours, preferably within 12 hours (but typically after at least 6 hours). For instance, the pharmaceutical composition may be administered at -24hrs and -12hrs before administration of the vaccine or gene therapy composition replacement product at Ohrs.

According to a particular preference, the compound of the present invention is for use in increasing efficacy of a vaccine in an individual, wherein the vaccine comprises the viral vector as defined herein, preferably wherein the pharmaceutical composition is administered to the individual prior to or concurrently with administration of the vaccine.

According to a further particular preference, the compound of the present invention is for use in increasing efficacy of a gene therapy composition in an individual, wherein the gene therapy composition comprises the viral vector as defined herein, preferably wherein the pharmaceutical composition is administered to the individual prior to or concurrently with administration of the gene therapy composition.

In embodiments, one or more antibodies are present in the individual which are specific for at least one occurrence of peptide P, or for peptide P _a and/or peptide Pb, preferably wherein said antibodies are neutralizing antibodies for said viral vector.

It is highly preferred that the composition is non- immunogenic in the individual (e.g. it does not comprise an adjuvant or an immunostimulatory substance that stimulates the innate or the adaptive immune system, e.g. such as an adjuvant or a T-cell epitope).

The composition of the present invention may be administered at a dose of 1-1000 mg, preferably 2-500 mg, more preferably 3- 250 mg, even more preferably 4-100 mg, especially 5-50 mg, compound per kg body weight of the individual, preferably wherein the composition is administered repeatedly. Such administration may be intraperitoneally, subcutaneously, intramuscularly or intravenously.

In an aspect, the present invention relates to a method of sequestering (or depleting) one or more antibodies (preferably wherein said antibodies are neutralizing antibodies for said viral vector) present in an individual, comprising obtaining a pharmaceutical composition as defined herein, wherein the composition is non-immunogenic in the individual and wherein the one or more antibodies present in the individual are specific for at least one occurrence of P, or for peptide P _a and/or peptide Pt; and administering (in particular repeatedly administering, e.g. at least two times, preferably at least three times, more preferably at least five times) the pharmaceutical composition to the individual.

In the context of the present invention, the individual (to be treated) may be a non-human animal, preferably a non-human primate, a sheep, a pig, a dog or a rodent, in particular a mouse.

Preferably, the biopolymer scaffold is autologous with respect to the individual, preferably wherein the biopolymer scaffold is an autologous protein (i.e. murine albumin is used when the individual is a mouse).

In embodiments, the individual is healthy.

In yet another aspect, the present invention relates to a pharmaceutical composition (i.e. a vaccine or gene therapy composition), comprising the compound defined herein and further comprising the viral vector and optionally at least one pharmaceutically acceptable excipient. The viral vector typically comprises a peptide fragment with a sequence length of at least six, preferably at least seven, more preferably at least eight, especially at least 9 amino acids. The sequence of at least one occurrence of peptide P, or peptide P _a and/or peptide Pb, of the compound is at least 70% identical, preferably at least 75% identical, more preferably at least 80% identical, yet more preferably at least 85% identical, even more preferably at least 90% identical, yet even more preferably at least 95% identical, especially completely identical to the sequence of said peptide fragment. Preferably, this pharmaceutical composition is for use in vaccination or gene therapy and/or for use in prevention or inhibition of an undesirable immune reaction against the viral vector.

This composition is furthermore preferably non-immunogenic in the individual.

In even yet another aspect, the present invention provides a method of inhibiting a (undesirable) - especially humoral - immune reaction to a treatment with a vaccine or gene therapy composition in an individual in need of treatment with the vaccine or gene therapy composition as defined above or of inhibiting neutralization of a viral vector in a vaccine or gene therapy composition as defined above for an individual in need of treatment with the vaccine or gene therapy composition, comprising obtaining said vaccine or gene therapy composition ; wherein the compound of the vaccine or gene therapy composition is non-immunogenic in the individual, and administering (preferably repeatedly administering) the vaccine or gene therapy composition to the individual.

In general, screening for peptide mimotopes per se is known in the art, see for instance Shanmugam et al. Mimotope-based compounds of the invention have the following two advantages over compounds based on wild-type epitopes: First, the undesired antibodies, as a rule, have even higher affinities for mimotopes found by screening a peptide library, leading to higher clearance efficiency of the mimotope-based compound. Second, mimotopes further enable avoiding T-cell epitope activity as much as possible (as described hereinabove) in case the wildtype epitope sequence induces such T-cell epitope activity.

In a further aspect, the present invention relates to a peptide, wherein the peptide is defined as disclosed herein for any one of the at least two peptides of the inventive compound, P, P _a , or P _b .

In certain embodiments, such peptides may be used as probes for the diagnostic typing and analysis of circulating viral vector-neutralizing antibodies. The peptides can e.g. be used as part of a diagnostic vector-neutralizing antibody typing or screening device or kit or procedure, as a companion diagnostic, for patient stratification or for monitoring vector-neutralizing antibody levels prior to, during and/or after vaccination or gene therapy.

In a further aspect, the invention relates to a method for detecting and/or quantifying antibodies in a biological sample comprising the steps of

- bringing the sample into contact with the peptide defined as disclosed herein (e.g. for P, P _a , or P _b ), and - detecting the presence and/or concentration of antibodies in the sample.

The skilled person is familiar with methods for detecting and/or quantifying antibodies in biological samples. The method can e.g. be a sandwich assay, preferably an enzyme-linked immunosorbent assay (ELISA), or a surface plasmon resonance (SPR) assay.

In a preference, the peptide (especially at least 10, more preferably at least 100, even more preferably at least 1000, especially at least 10000 different peptides of the invention) is immobilized on a solid support, preferably an ELISA plate or an SPR chip or a biosensor-based diagnostic device with an electrochemical, fluorescent, magnetic, electronic, gravimetric or optical biotransducer. Alternatively, or in addition thereto, the peptide (especially at least 10, more preferably at least 100, even more preferably at least 1000, especially at least 10000 different peptides of the invention) may be coupled to a reporter or reporter fragment, such as a reporter fragment suitable for a protein-fragment complementation assay (PCA); see e.g. Li et al, 2019, or Kainulainen et al, 2021.

Preferably, the sample is obtained from a mammal, preferably a human. Preferably the sample is a blood sample, preferably a whole blood, serum, or plasma sample.

The invention further relates to the use of a peptide defined as disclosed herein (e.g. for P, P _a , or Pb) in a diagnostic assay, preferably ELISA, preferably as disclosed herein above.

A further aspect of the invention relates to a diagnostic device comprising the peptide defined as disclosed herein (e.g. for P, P _a , or Pb), preferably immobilized on a solid support. In a preference, the solid support is an ELISA plate or a surface plasmon resonance chip. In another preference, the diagnostic device is a biosensor-based diagnostic device with an electrochemical, fluorescent, magnetic, electronic, gravimetric or optical biotransducer.

In another preferred embodiment, the diagnostic device is a lateral flow assay. The invention further relates to a diagnostic kit comprising a peptide defined as disclosed herein (e.g. for P, P _a , or Pb), preferably a diagnostic device as defined herein. Preferably the diagnostic kit further comprises one or more selected from the group of a buffer, a reagent, instructions. Preferably the diagnostic kit is an ELISA kit.

A further aspect relates to an apheresis device comprising the peptide defined as disclosed herein (e.g. for P, P _a , or Pb). Preferably the peptide is immobilized on a solid carrier. It is especially preferred if the apheresis device comprises at least two, preferably at least three, more preferably at least four different peptides defined as disclosed herein (e.g. for P, P _a , or Pb). In a preferred embodiment the solid carrier comprises the inventive compound.

Preferably, the solid carrier is capable of being contacted with blood or plasma flow. Preferably, the solid carrier is a sterile and pyrogen-free column.

In the context of the present invention, for improved bioavailability, it is preferred that the inventive compound has a solubility in water at 25°C of at least 0.1 μg/ml, preferably at least 1 μg/ml, more preferably at least 10 μg/ml, even more preferably at least 100 μg/ml, especially at least 1000 μg/ml.

The term "preventing" or "prevention" as used herein means to stop a disease state or condition from occurring in a patient or subject completely or almost completely or at least to a (preferably significant) extent, especially when the patient or subject or individual is predisposed to such a risk of contracting a disease state or condition.

The pharmaceutical composition of the present invention is preferably provided as a (typically aqueous) solution, (typically aqueous) suspension or (typically aqueous) emulsion. Excipients suitable for the pharmaceutical composition of the present invention are known to the person skilled in the art, upon having read the present specification, for example water (especially water for injection), saline, Ringer's solution, dextrose solution, buffers, Hank solution, vesicle forming compounds (e.g. lipids), fixed oils, ethyl oleate, 5% dextrose in saline, substances that enhance isotonicity and chemical stability, buffers and preservatives. Other suitable excipients include any compound that does not itself induce the production of antibodies in the patient (or individual) that are harmful for the patient (or individual). Examples are well tolerable proteins, polysaccharides, polylactic acids, polyglycolic acid, polymeric amino acids and amino acid copolymers. This pharmaceutical composition can (as a drug) be administered via appropriate procedures known to the skilled person (upon having read the present specification) to a patient or individual in need thereof (i.e. a patient or individual having or having the risk of developing the diseases or conditions mentioned herein). The preferred route of administration of said pharmaceutical composition is parenteral administration, in particular through intraperitoneal, subcutaneous, intramuscular and/or intravenous administration. For parenteral administration, the pharmaceutical composition of the present invention is preferably provided in injectable dosage unit form, e.g. as a solution (typically as an aqueous solution), suspension or emulsion, formulated in conjunction with the above-defined pharmaceutically acceptable excipients. The dosage and method of administration, however, depends on the individual patient or individual to be treated. Said pharmaceutical composition can be administered in any suitable dosage known from other biological dosage regimens or specifically evaluated and optimised for a given individual. For example, the active agent may be present in the pharmaceutical composition in an amount from 1 mg to 10 g, preferably 50 mg to 2 g, in particular 100 mg to 1 g. Usual dosages can also be determined on the basis of kg body weight of the patient, for example preferred dosages are in the range of 0.1 mg to 100 mg/kg body weight, especially 1 to 10 mg/kg body weight (per administration session). The administration may occur e.g. once daily, once every other day, once per week or once every two weeks. As the preferred mode of administration of the inventive pharmaceutical composition is parenteral administration, the pharmaceutical composition according to the present invention is preferably liquid or ready to be dissolved in liquid such sterile, de-ionised or distilled water or sterile isotonic phosphate-buffered saline (PBS). Preferably, 1000 μg (dry-weight) of such a composition comprises or consists of 0.1- 990 μg, preferably l-900μg, more preferably 10- 200μg compound, and option-ally 1-500 μg, preferably 1-100 μg, more preferably 5-15 μg (buffer) salts (preferably to yield an isotonic buffer in the final volume), and optionally 0.1-999.9 μg, preferably 100-999.9 μg, more preferably 200-999 μg other excipients. Preferably, 100 mg of such a dry composition is dissolved in sterile, de-ionised/distilled water or sterile isotonic phosphate-buffered saline (PBS) to yield a final volume of 0.1- 100 ml, preferably 0.5-20 ml, more preferably 1-10 ml.

It is evident to the skilled person that active agents and drugs described herein can also be administered in salt-form (i.e. as a pharmaceutically acceptable salt of the active agent). Accordingly, any mention of an active agent herein shall also include any pharmaceutically acceptable salt forms thereof.

Methods for chemical synthesis of peptides used for the compound of the present invention are well-known in the art. Of course, it is also possible to produce the peptides using recombinant methods. The peptides can be produced in microorganisms such as bacteria, yeast or fungi, in eukaryotic cells such as mammalian or insect cells, or in a recombinant virus vector such as adenovirus, poxvirus, herpesvirus, Simliki forest virus, baculovirus, bacteriophage, sindbis virus or sendai virus. Suitable bacteria for producing the peptides include E. coli, B. subtilis or any other bacterium that is capable of expressing such peptides. Suitable yeast cells for expressing the peptides of the present invention include Saccharomyces cerevisiae, Schizosaccharomyces pombe, Candida, Pichiapastoris or any other yeast capable of expressing peptides. Corresponding means and methods are well known in the art. Also, methods for isolating and purifying recombinantly produced peptides are well known in the art and include e.g. gel filtration, affinity chromatography, ion exchange chromatography etc.

Beneficially, cysteine residues are added to the peptides at the N- and/or C-terminus to facilitate coupling to the biopolymer scaffold, especially.

To facilitate isolation of said peptides, fusion polypeptides may be made wherein the peptides are translationally fused (covalently linked) to a heterologous polypeptide which enables isolation by affinity chromatography. Typical heterologous polypeptides are His-Tag (e.g. His6; 6 histidine residues), GST-Tag (Glutathione-S-transferase) etc. The fusion polypeptide facilitates not only the purification of the peptides but can also prevent the degradation of the peptides during the purification steps. If it is desired to remove the heterologous polypeptide after purification, the fusion polypeptide may comprise a cleavage site at the junction between the peptide and the heterologous polypeptide. The cleavage site may consist of an amino acid sequence that is cleaved with an enzyme specific for the amino acid sequence at the site (e.g. proteases).

The coupling/conjugation chemistry used to link the peptides / peptide n-mers to the biopolymer scaffold (e.g. via heterobifunctional compounds such as GMBS and of course also others as described in "Bioconjugate Techniques", Greg T. Hermanson) or used to conjugate the spacer to the peptides in the context of the present invention can also be selected from reactions known to the skilled in the art. The biopolymer scaffold itself may be recombinantly produced or obtained from natural sources.

Herein, the term "specific for" - as in "molecule A specific for molecule B" - means that molecule A has a binding preference for molecule B compared to other molecules in an individual's body. Typically, this entails that molecule A (such as an antibody) has a dissociation constant (also called "affinity") in regard to molecule B (such as the antigen, specifically the binding epitope thereof) that is lower than (i.e. "stronger than") 1000 nM, preferably lower than 100 nM, more preferably lower than 50 nM, even more preferably lower than 10 nM, especially lower than 5 nM.

Herein, "UniProt" refers to the Universal Protein Resource. UniProt is a comprehensive resource for protein sequence and annotation data. UniProt is a collaboration between the European Bioinformatics Institute (EMBL-EBI), the SIB Swiss Institute of Bioinformatics and the Protein Information Resource (PIR). Across the three institutes more than 100 people are involved through different tasks such as database curation, software development and support. Website: http://www.uniprot.org/

Entries in the UniProt databases are identified by their accession codes (referred to herein e.g. as "UniProt accession code" or briefly as "UniProt" followed by the accession code), usually a code of six alphanumeric letters (e.g. "Q1HVF7"). If not specified otherwise, the accession codes used herein refer to entries in the Protein Knowledgebase (UniProtKB) of UniProt. If not stated otherwise, the UniProt database state for all entries referenced herein is of 23 September 2020 (UniProt/UniProtKB Release 2020_04).

In the context of the present application, sequence variants (designated as "natural variant" in UniProt) are expressly included when referring to a UniProt database entry.

"Percent (%) amino acid sequence identity" or "X% identical" (such as "70% identical") with respect to a reference polypeptide or protein sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, ALIGN-2, Megalign (DNASTAR) or the "needle" pairwise sequence alignment application of the EMBOSS software package. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are calculated using the sequence alignment of the computer programme "needle" of the EMBOSS software package (publicly available from European Molecular Biology Laboratory; Rice et al., 2000).

The needle programme can be accessed under the web site http://www.ebi.ac.uk/Tools/psa/emboss_needle/ or downloaded for local installation as part of the EMBOSS package from http://emboss.sourceforge.net/. It runs on many widely-used UNIX operating systems, such as Linux.

To align two protein sequences, the needle programme is preferably run with the following parameters:

Commandline: needle -auto -stdout -asequence SEQUENCE_FILE_A -bsequence SEQUENCE_FILE_B -datafile EBLOSUM62 - gapopen 10.0 -gapextend 0.5 -endopen 10.0 -endextend 0.5 - aformatS pair -sproteinl -sprotein2 (Align_format: pair Report_file: stdout)

The % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows:

100 times the fraction X/Y where X is the number of amino acid residues scored as identical matches by the sequence alignment program needle in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. In cases where "the sequence of A is more than N% identical to the entire sequence of B", Y is the entire sequence length of B (i.e. the entire number of amino acid residues in B). Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the needle computer program.

The present invention further relates to the following embodiments:

Embodiment 1. A compound comprising

- a biopolymer scaffold and at least

- a first peptide n-mer of the general formula:

P ( - S - P ) _(n-1 ) and - a second peptide n-mer of the general formula:

P ( - S - P ) _(n-1 ) ; wherein, independently for each occurrence, P is a peptide with a sequence length of 6-13 amino acids, and S is a nonpeptide spacer, wherein, independently for each of the peptide n-mers, n is an integer of at least 1, preferably of at least 2, more preferably of at least 3, especially of at least 4, wherein each of the peptide n-mers is bound to the biopolymer scaffold, preferably via a linker each, wherein, independently for each occurrence, P has an aminoacid sequence comprising a sequence fragment with a length of at least six (preferably at least 7, more preferably at least 8, especially at least 9) amino acids of a capsid protein sequence of a viral vector, in particular of an AdV hexon protein sequence, an AdV fiber protein sequence, an AdV penton protein sequence, an AdV Illa protein sequence, an AdV VI protein sequence, an AdV VIII protein sequence or an AdV IX protein sequence or of any one of the capsid protein sequences identified in Fig. 10 and Fig. 11 or of any one of the capsid protein sequences listed in Cearley et al., 2008, optionally wherein at most three, preferably at most two, most preferably at least one amino acid of the sequence fragment is independently substituted by any other amino acid.

Embodiment 2. The compound of embodiment 1, wherein at least one occurrence of P is a circularized peptide, preferably wherein at least 10% of all occurrences of P are circularized peptides, more preferably wherein at least 25% of all occurrences of P are circularized peptides, yet more preferably wherein at least 50% of all occurrences of P are circularized peptides, even more preferably wherein at least 75% of all occurrences of P are circularized peptides, yet even more preferably wherein at least 90% of all occurrences of P are circularized peptides or even wherein at least 95% of all occurrences of P are circularized peptides, especially wherein all of the occurrences of P are circularized peptides. Embodiment 3. The compound of embodiment 1 or 2, wherein, independently for each of the peptide n-mers, n is at least 2, more preferably at least 3, especially at least 4.

Embodiment 4. The compound of any one of embodiments 1 to 3, wherein, independently for each of the peptide n-mers, n is less than 10, preferably less than 9, more preferably less than 8, even more preferably less than 7, yet even more preferably less than 6, especially less than 5.

Embodiment 5. The compound of any one of embodiments 1 to 4, wherein, for each of the peptide n-mers, n is 2.

Embodiment 6. The compound of any one of embodiments 1 to 5, wherein at least one occurrence of P is P _a and/or at least one occurrence of P is Pb, wherein P _a is a peptide with a sequence length of 6-13 amino acids, preferably 7-11 amino acids, more preferably 7-9 amino acids, wherein P _b is a peptide with a sequence length of 6-13 amino acids, preferably 7-11 amino acids, more preferably 7-9 amino acids.

Embodiment 7. The compound of any one of embodiments 1 to 6, wherein, independently for each occurrence, P is P _a or P _b .

Embodiment 8. The compound of any one of embodiments 1 to 7, wherein, in the first peptide n-mer, each occurrence of P is P _a and, in the second peptide n-mer, each occurrence of P is P _b .

Embodiment 9. The compound of any one of embodiments 1 to 8, wherein the first peptide n-mer is P _a - S - P _a and the second peptide n-mer is P _a - S - P _a ; or the first peptide n-mer is P _a - S - P _a and the second peptide n-mer is P _b - S - P _b ; the first peptide n-mer is P _b - S - P _b and the second peptide n-mer is P _b - S - Pb," the first peptide n-mer is P _a - S - P _b and the second peptide n-mer is P _a - S - Pb," the first peptide n-mer is P _a - S - P _b and the second peptide n-mer is P _a - S - P _a ; or the first peptide n-mer is P _a - S - P _b and the second peptide n-mer is P _b - S - Pb.

Embodiment 10.A compound comprising

- a biopolymer scaffold and at least

- a first peptide n-mer which is a peptide dimer of the formula P _a — S — P _a or P _a — S — Pb, wherein P _a is a peptide with a sequence length of 6-13 amino acids, preferably 7-11 amino acids, more preferably 7-9 amino acids, P _b is a peptide with a sequence length of 6-13 amino acids, preferably 7-11 amino acids, more preferably 7-9 amino acidss, and S is a non-peptide spacer, wherein the first peptide n-mer is bound to the biopolymer scaffold, preferably via a linker, wherein P _a has an amino-acid sequence comprising a sequence fragment with a length of at least six, preferably at least seven, more preferably at least eight, especially at least 9 (or 10, 11, 12 or 13) amino acids of a capsid protein sequence of a (non-pathogenic) viral vector, in particular of an AdV hexon protein sequence, an AdV fiber protein sequence, an AdV penton protein sequence, an AdV Illa protein sequence, an AdV VI protein sequence, an AdV VIII protein sequence or an AdV IX protein sequence or of any one of the capsid protein sequences identified in Fig. 10 and Fig. 11 or of any one of the capsid protein sequences listed in Cearley et al., 2008, optionally wherein at most three, preferably at most two, most preferably at least one amino acid of the sequence fragment is independently substituted by any other amino acid.

Embodiment 11. The compound of embodiment 10, further comprising a second peptide n-mer which is a peptide dimer of the formula Pb - S - P _b or P _a - S - Pb, wherein the second peptide n-mer is bound to the biopolymer scaffold, preferably via a linker, wherein P _b has an amino-acid sequence comprising a sequence fragment with a length of at least six, preferably at least seven, more preferably at least eight, especially at least 9 (or 10, 11, 12 or 13) amino acids of a capsid protein sequence of a (non-pathogenic) viral vector, in particular of an AdV hexon protein sequence, an AdV fiber protein sequence, an AdV penton protein sequence, an AdV Illa protein sequence, an AdV VI protein sequence, an AdV VIII protein sequence or an AdV IX protein sequence or of any one of the capsid protein sequences identified in Fig. 10 and Fig. 11 or of any one of the capsid protein sequences listed in Cearley et al., 2008, optionally wherein at most three, preferably at most two, most preferably at least one amino acid of the sequence fragment is independently substituted by any other amino acid.

Embodiment 12. The compound of any one of embodiments 1 to 9 and 11, wherein the first peptide n-mer is different from the second peptide n-mer.

Embodiment 13. The compound of any one of embodiments 6 to 12, wherein the peptide P _a is different from the peptide Pb, preferably wherein the peptide P _a and the peptide P _b are two different epitopes of the same capsid antigen or two different epitope parts of the same capsid epitope.

Embodiment 14. The compound of any one of embodiments 6 to 13, wherein the peptide P _a and the peptide P _b comprise the same amino-acid sequence fragment, wherein the amino-acid sequence fragment has a length of at least 2 amino acids, preferably at least 3 amino acids, more preferably at least 4 amino acids, yet more preferably at least 5 amino acids, even more preferably at least 6 amino acids, yet even more preferably at least 7 amino acids, especially at least 8 amino acids or even at least 9 amino acids.

Embodiment 15. The compound of any one of embodiments 6 to 14, wherein P _a and/or P _b is circularized.

Embodiment 16. The compound of any one of embodiments 1 to 15, wherein the compound comprises a plurality of said first peptide n-mer and/or a plurality of said second peptide n-mer.

Embodiment 17. The compound of any one of embodiments 1 to 16, wherein the biopolymer scaffold is a protein, preferably a mammalian protein such as a human protein, a non-human primate protein, a sheep protein, a pig protein, a dog protein or a rodent protein.

Embodiment 18. The compound of embodiment 17, wherein the biopolymer scaffold is a globulin. Embodiment 19. The compound of embodiment 18, wherein the biopolymer scaffold is selected from the group consisting of immunoglobulins, alphal-globulins, alpha2-globulins and betaglobulins.

Embodiment 20. The compound of embodiment 19, wherein the biopolymer scaffold is selected from the group consisting of immunoglobulin G, haptoglobin and transferrin.

Embodiment 21. The compound of embodiment 20, wherein the biopolymer scaffold is haptoglobin.

Embodiment 22. The compound of embodiment 17, wherein the biopolymer scaffold is an albumin.

Embodiment 23. The compound of any one of embodiments 1 to 22, wherein the compound is non-immunogenic in a mammal, preferably in a human, in a non-human primate, in a sheep, in a pig, in a dog or in a rodent.

Embodiment 24. The compound of any one of embodiments 1 to 23, wherein the compound is for intracorporeal sequestration (or intracorporeal depletion) of at least one antibody (against the viral vector or neutralizing the viral vector) in an individual, preferably in the bloodstream of the individual and/or for reduction of the titre of at least one antibody (against the viral vector or neutralizing the viral vector) in the individual, preferably in the bloodstream of the individual. Embodiment 25. The compound of any one of embodiments 1 to 24, wherein the viral vector is an adenovirus (AdV) vector or an adeno-associated virus (AAV) vector.

Embodiment 26. The compound of any one of embodiments 1 to 25, wherein the entire sequence, optionally with the exception of an N-terminal and/or C-terminal cysteine, of at least one occurrence of P, preferably of at least 10% of all occurrences of P, more preferably of at least 25% of all occurrences of P, yet more preferably of at least 50% of all occurrences of P, even more preferably of at least 75% of all occurrences of P, yet even more preferably of at least 90% of all occurrences of P or even of at least 95% of all occurrences of P, especially of all of the occurrences of P, is identical to a sequence fragment of a protein, wherein the protein is identified by one of the following UniProt accession codes: A9RAI0, B5SUY7, 041855, 056137, 056139, P03135, P04133, P04882, P08362, P10269, P12538, P69353, Q5Y9B2, Q5Y9B4, Q65311, Q6JC40, Q6VGT5, Q8JQF8, Q8JQG0, Q98654, Q9WBP8, Q9YIJ1, or of an AdV hexon protein, an AdV fiber protein, an AdV penton protein, an AdV Illa protein, an AdV VI protein, an AdV VIII protein or an AdV IX protein or of any one of the capsid proteins identified in Fig. 10 and Fig. 11 or of any one of the capsid proteins listed in Cearley et al., 2008; optionally wherein the sequence fragment comprises at most three, even more preferably at most two, especially at most one amino acid substitutions.

Embodiment 27. The compound of any one of embodiments 1 to 26, wherein the entire sequence, optionally with the exception of an N-terminal and/or C-terminal cysteine, of peptide P _a is identical to a sequence fragment of a protein, wherein the protein is identified by one of the UniProt accession codes listed in embodiment 26; optionally wherein the sequence fragment comprises at most three, even more preferably at most two, especially at most one amino acid substitutions.

Embodiment 28. The compound of any one of embodiments 1 to 27, wherein the entire sequence, optionally with the exception of an N-terminal and/or C-terminal cysteine, of peptide P _b is identical to a sequence fragment of a protein, wherein the protein is identified by one of the UniProt accession codes listed in embodiment 26; optionally wherein the sequence fragment comprises at most three, even more preferably at most two, especially at most one amino acid substitutions.

Embodiment 29. The compound of any one of embodiments 1 to 28, wherein the entire sequence, optionally with the exception of an N-terminal and/or C-terminal cysteine, of peptide P _a is identical to a sequence fragment of a protein and the entire sequence, optionally with the exception of an N-terminal and/or C-terminal cysteine, of peptide P _b is identical to the same or another, preferably another, sequence fragment of the same protein, wherein the protein is identified by one of the UniProt accession codes listed in embodiment 26; optionally wherein the sequence fragment comprises at most three, even more preferably at most two, especially at most one amino acid substitutions.

Embodiment 30. The compound of any one of embodiments 1 to 29, wherein said sequence fragment comprises a sequence of at least 4 or at least 5 or at least 6, preferably at least 7, more preferably at least 8, even more preferably at least 9, yet even more preferably at least 10 consecutive amino acids selected from: the group of AdV sequences ETGPPTVPFLTPPF (SEQ ID NO: 32), HDSKLSIATQGPL (SEQ ID NO: 33), LNLRLGQGPLFINSAHNLDINY (SEQ ID NO: 34), VDPMDEPTLLYVLFEVFDW (SEQ ID NO: 35), MKRARPSEDTFNPVYPYD (SEQ ID NO: 36), ISGTVQSAHLIIRFD (SEQ ID NO: 37), LGQGPLFINSAHNLDINYNKGLYLF (SEQ ID NO: 38), SYPFDAQNQLNLRLGQGPLFIN (SEQ ID NO: 39), GDTTPSAYSMSFSWDWSGHNYIN (SEQ ID NO: 40), VLLNNSFLDPEYWNFRN (SEQ ID NO: 41), HNYINEIFATSSYTFSYIA (SEQ ID NO: 42), DEAATALEINLEEEDDDNEDEVDEQAEQQKTH (SEQ ID NO: 43), INLEEEDDDNEDEVDEQAEQ (SEQ ID NO: 44), DNEDEVDEQAEQQKTHVF (SEQ ID NO: 45), EWDEAATALEINLEE (SEQ ID NO: 46), PKW LYSEDVDIETPDTHISYMP (SEQ ID NO: 47), YIPESYKDRMYSFFRNF (SEQ ID NO: 48), DSIGDRTRYFSMW (SEQ ID NO: 49), SYKDRMYSFFRNF (SEQ ID NO: 50), and FLVQMLANYNIGYQGFY (SEQ ID NO: 51), or the group of AAV sequences WQNRDVYLQGPIWAKIP (SEQ ID NO: 52), DNTYFGYSTPWGYFDFNRFHC (SEQ ID NO: 53), MANQAKNWLPGPCY (SEQ ID NO: 54), LPYVLGSAHQGCLPPFP (SEQ ID NO: 55), NGSQAVGRSSFYCLEYF (SEQ ID NO: 56), PLIDQYLYYL (SEQ ID NO: 57), EERFFPSNGILIF (SEQ ID NO: 58) ADGVGSSSGNWHC (SEQ ID NO: 59), SEQ ID NOs: 383-1891 (see Table 1) - preferably group III of Table 1, more preferably group II of Table 1, especially group I of Table 1 - and SEQ ID NOs: 1892-2063 (see Table 2) - preferably group I of Table 2 - and sequences of group II or III of Table 3 (in particular SEQ ID NOs: 2064-2103), more preferably sequences of group I of Table 3, or the group of sequences of Table 4, in particular the group of sequences identified by SEQ ID NOs: 2104-2190; optionally wherein at most three, preferably at most two, most preferably at least one amino acid of the sequence fragment is independently substituted by any other amino acid.

Embodiment 31. The compound of any one of embodiments 1 to 30, wherein, independently for each occurrence, P comprises a 6- amino-acid fragment, preferably a 7-amino-acid-fragment, more preferably a 8-amino-acid-fragment, even more preferably a 9- amino-acid fragment, yet even more preferably a 10-amino-acid fragment, especially an entire sequence selected from the group of sequences consisting of GPPTVPFLTP (SEQ ID NO: 60), ETGPPTVPFLTPP (SEQ ID NO: 61), TGPPTVPFLT (SEQ ID NO: 62), PTVPFLTPPF (SEQ ID NO: 63), HDSKLSIATQGPL (SEQ ID NO: 64), SIATQGP (SEQ ID NO: 65), NLRLGQGPLF (SEQ ID NO: 66), QGPLFINSAH (SEQ ID NO: 67), PLFINSAHNLD (SEQ ID NO: 68), LGQGPLF (SEQ ID NO: 69), LNLRLGQGPL (SEQ ID NO: 70), GQGPLFI (SEQ ID NO: 71), NLRLGQGPLFINS (SEQ ID NO: 72), LFINSAHNLDINY (SEQ ID NO: 73), FINSAHNLDI (SEQ ID NO: 74), LRLGQGPLFI (SEQ ID NO: 75),

GPLFINSAHN (SEQ ID NO: 76), DEPTLLYVLFEVF (SEQ ID NO: 77),

TLLYVLFEVF (SEQ ID NO: 78), DEPTLLYVLF (SEQ ID NO: 79),

TLLYVLFEVFDW (SEQ ID NO: 80), TLLYVLF (SEQ ID NO: 81),

MDEPTLLYVLFEV (SEQ ID NO: 82), EPTLLYVLFE (SEQ ID NO: 83),

DPMDEPTLLYVLF (SEQ ID NO: 84), LLYVLFEVFD (SEQ ID NO: 85),

YVLFEVFDW (SEQ ID NO: 86), PTLLYVLFEV (SEQ ID NO: 87), PTLLYVLFEVFDV (SEQ ID NO: 88), LYVLFEVFDV (SEQ ID NO: 89),

EPTLLYVLFEVFD (SEQ ID NO: 90), LYVLFEV (SEQ ID NO: 91),

PMDEPTLLYVLFE (SEQ ID NO: 92), LLYVLFE (SEQ ID NO: 93),

VDPMDEPTLLYVL (SEQ ID NO: 94), YVLFEVF (SEQ ID NO: 95), PTLLYVL

(SEQ ID NO: 96), MKRARPSEDTF (SEQ ID NO: 97), KRARPSEDTF (SEQ ID

NO: 98), MKRARPSEDT (SEQ ID NO: 99), MKRARPSEDTFN (SEQ ID NO: 100), ARPSEDTFNP (SEQ ID NO: 101), RARPSEDTFN (SEQ ID NO: 102), RPSEDTF (SEQ ID NO: 103), MKRARPSEDTFNP (SEQ ID NO: 104),

RARPSEDTFNPVY (SEQ ID NO: 105), ARPSEDT (SEQ ID NO: 106),

EDTFNPVYPY (SEQ ID NO: 107), RPSEDTFNPVYPY (SEQ ID NO: 108), KRARPSEDTFNPV (SEQ ID NO: 109), DTFNPVY (SEQ ID NO: 110),

RPSEDTFNPV (SEQ ID NO: 111), PSEDTFNPVY (SEQ ID NO: 112),

DTFNPVYPYD (SEQ ID NO: 113), VQSAHLIIRF (SEQ ID NO: 114),

AHLIIRF (SEQ ID NO: 115), SGTVQSAHLIIRE (SEQ ID NO: 116),

TVQSAHLIIR (SEQ ID NO: 117), HLIIRFD (SEQ ID NO: 118), SAHLIIR (SEQ ID NO: 119), QSAHLIIRFD (SEQ ID NO: 120), ISGTVQSAHLIIR (SEQ ID NO: 121), GTVQSAHLII (SEQ ID NO: 122), GTVQSAHLIIRFD (SEQ ID NO: 123), QSAHLII (SEQ ID NO: 124), HNLDINY (SEQ ID NO: 125), LFINSAHNLDINY (SEQ ID NO: 126), NLDINYNKGLYLF (SEQ ID NO: 127), FVSPNG (SEQ ID NO: 128), NYINEIF (SEQ ID NO: 129), NKGLYLF (SEQ ID NO: 130), INYNKGLYLF (SEQ ID NO: 131), NSAHNLDINY (SEQ ID NO: 132), WDWSGHNYINEIF (SEQ ID NO: 133), SGHNYINEIF (SEQ ID NO: 134), LGTGLSF (SEQ ID NO: 135), PFLTPPF (SEQ ID NO: 136), LGQGPLF (SEQ ID NO: 137), NLRLGQGPLF (SEQ ID NO: 138), NQLNLRLGQGPLF (SEQ ID NO: 139), GQGPLFI (SEQ ID NO: 140), QLNLRLGQGPLFI (SEQ ID NO: 141), SYPFDAQNQLNLR (SEQ ID NO: 142), YPFDAQNQLNLRL (SEQ ID NO: 143), LRLGQGPLFI (SEQ ID NO: 144), NQLNLRL (SEQ ID NO: 145), FDAQNQLNLR (SEQ ID NO: 146), QNQLNLR (SEQ ID NO: 147), QGPLFIN (SEQ ID NO: 148), PFDAQNQLNLRLG (SEQ ID NO: 149), DAQNQLNLRL (SEQ ID NO: 150), RLGQGPLFIN (SEQ ID NO: 151), QLNLRLG (SEQ ID NO: 152), FDAQNQLNLRLGQ (SEQ ID NO: 153), LNLRLGQGPLFIN (SEQ ID NO: 154), AQNQLNLRLG (SEQ ID NO: 155), AQNQLNL (SEQ ID NO: 156), LNLRLGQ (SEQ ID NO: 157), SYPFDAQNQL (SEQ ID NO: 158), PFDAQNQLNL (SEQ ID NO: 159), YSMSFSW (SEQ ID NO: 160), TPSAYSMSFSWDW (SEQ ID NO: 161), MSFSWDW (SEQ ID NO: 162), PSAYSMSFSW (SEQ ID NO: 163), DTTPSAYSMSFSW (SEQ ID NO: 164), TTPSAYSMSF (SEQ ID NO: 165), YSMSFSWDWS (SEQ ID NO: 166), TGDTTPSAYSMSF (SEQ ID NO: 167), FSWDWSGHNY (SEQ ID NO: 168), SFSWDWS (SEQ ID NO: 169), SAYSMSF (SEQ ID NO: 170), SFSWDWSGHN (SEQ ID NO: 171), SAYSMSFSWD (SEQ ID NO: 172), SMSFSWD (SEQ ID NO: 173), SWDWSGHNYI (SEQ ID NO: 174), AYSMSFS (SEQ ID NO: 175), SMSFSWDWSGHNY (SEQ ID NO: 176), FSWDWSG (SEQ ID NO: 177), SWDWSGH (SEQ ID NO: 178), FLDPEYWNFR (SEQ ID NO: 179), SFLDPEYWNF (SEQ ID NO: 180), PEYWNFR (SEQ ID NO: 181), LNNSFLDPEYWNF (SEQ ID NO: 182), NNSFLDPEYWNFR (SEQ ID NO: 183), FLDPEYW (SEQ ID NO: 184), DPEYWNF (SEQ ID NO: 185), NNSFLDPEYW (SEQ ID NO: 186), VLLNNSFLDPEYW (SEQ ID NO: 187), EYWNFRN (SEQ ID NO: 188), LNNSFLDPEY (SEQ ID NO: 189), LDPEYWNFRN (SEQ ID NO: 190), LNNSFLD (SEQ ID NO: 191), NSFLDPEYWN (SEQ ID NO: 192), SSYTFSY (SEQ ID NO: 193), FATSSYTFSY (SEQ ID NO: 194), YINEIFATSSYTF (SEQ ID NO: 195), SYTFSYI (SEQ ID NO: 196), ATSSYTF (SEQ ID NO: 197), EIFATSSYTF (SEQ ID NO: 198), NEIFATSSYTFSY (SEQ ID NO: 199), ATSSYTFSYI (SEQ ID NO: 200), HNYINEIFATSSY (SEQ ID NO: 201), IFATSSY (SEQ ID NO: 202), INEIFATSSY (SEQ ID NO: 203), NYINEIFATSSYT (SEQ ID NO: 204), YINEIFA (SEQ ID NO: 205), YTFSYIA (SEQ ID NO: 206), EIFATSSYTFSYI (SEQ ID NO: 207), ALEINLEEEDDDN (SEQ ID NO: 208), ATALEINLEEEDD (SEQ ID NO: 209), EAATALEINLEEE (SEQ ID NO: 210), LEINLEE (SEQ ID NO: 211), TALEINLEEEDDD (SEQ ID NO: 212), EINLEEE (SEQ ID NO: 213), ALEINLEEED (SEQ ID NO: 214), LEINLEEEDD (SEQ ID NO: 215), TALEINLEEE (SEQ ID NO: 216), DEAATALEINLEE (SEQ ID NO: 217), LEINLEEEDDDNE (SEQ ID NO: 218), AATALEINLEEED (SEQ ID NO: 219), EINLEEEDDD (SEQ ID NO: 220), ATALEINLEE (SEQ ID NO: 221), INLEEEDDDN (SEQ ID NO: 222), NLEEEDDDNE (SEQ ID NO: 223), DEVDEQA (SEQ ID NO: 224), EDDDNEDEVDEQA (SEQ ID NO: 225), DDNEDEVDEQAEQ (SEQ ID NO: 226), EVDEQAE (SEQ ID NO: 227), DNEDEVDEQA (SEQ ID NO: 228), VDEQAEQ (SEQ ID NO: 229), EDEVDEQAEQQKT (SEQ ID NO: 230), EDEVDEQAEQ

(SEQ ID NO: 231), DEVDEQAEQQKTH (SEQ ID NO: 232), NEDEVDEQAEQQK

(SEQ ID NO: 233), DEVDEQAEQQ (SEQ ID NO: 234), EINLEEEDDDNED

(SEQ ID NO: 235), NLEEEDDDNEDEV (SEQ ID NO: 236), INLEEED (SEQ

ID NO: 237), LEEEDDDNED (SEQ ID NO: 238), INLEEEDDDNEDE (SEQ ID NO: 239), DDDNEDEVDEQAE (SEQ ID NO: 240), LEEEDDDNEDEVD (SEQ ID NO: 241), DDNEDEVDEQ (SEQ ID NO: 242), EDDDNED (SEQ ID NO: 243), NLEEEDD (SEQ ID NO: 244), DDNEDEV (SEQ ID NO: 245), DDDNEDEVDE (SEQ ID NO: 246), DDDNEDE (SEQ ID NO: 247), EEEDDDNEDE (SEQ ID

NO: 248), EEDDDNE (SEQ ID NO: 249), EDDDNEDEVD (SEQ ID NO: 250), EDEVDEQ (SEQ ID NO: 251), EEDDDNEDEVDEQ (SEQ ID NO: 252), EEDDDNEDEV (SEQ ID NO: 253), EEEDDDNEDEVDE (SEQ ID NO: 254),

EVDEQAEQQK (SEQ ID NO: 255), DNEDEVDEQAEQQ (SEQ ID NO: 256),

VDEQAEQQKT (SEQ ID NO: 257), EVDEQAEQQKTHV (SEQ ID NO: 258),

VDEQAEQQKTHVF (SEQ ID NO: 259), ALEINLE (SEQ ID NO: 260), WDEAATALEINLE (SEQ ID NO: 261), AATALEINLE (SEQ ID NO: 262),

EWDEAATALEINL (SEQ ID NO: 263), EAATALEINL (SEQ ID NO: 264),

LYSEDVDIET (SEQ ID NO: 265), LYSEDVDIETPDT (SEQ ID NO: 266),

KW LYSEDVDIET (SEQ ID NO: 267), IETPDTH (SEQ ID NO: 268), VDIETPDTHI (SEQ ID NO: 269), VLYSEDVDIE (SEQ ID NO: 270), DVDIETPDTHISY (SEQ ID NO: 271), W LYSEDVDIETP (SEQ ID NO: 272), SEDVDIETPDTHI (SEQ ID NO: 273), ETPDTHI (SEQ ID NO: 274), VLYSEDVDIETPD (SEQ ID NO: 275), DVDIETPDTH (SEQ ID NO: 276), DIETPDTHIS (SEQ ID NO: 277), EDVDIETPDTHIS (SEQ ID NO: 278), IETPDTHISY (SEQ ID NO: 279), YSEDVDIETPDTH (SEQ ID NO: 280), VDIETPDTHISYM (SEQ ID NO: 281), PKW LYSEDVDIE (SEQ ID NO: 282), DIETPDT (SEQ ID NO: 283), DIETPDTHISYMP (SEQ ID NO: 284), EDVDIETPDT (SEQ ID NO: 285), ETPDTHISYM (SEQ ID NO: 286), IETPDTHISYMP (SEQ ID NO: 287), DRMYSFFRNF (SEQ ID NO: 288), DRMYSFF (SEQ ID NO: 289), YSFFRNF (SEQ ID NO: 290), IPESYKDRMYSFF (SEQ ID NO: 291), SYKDRMYSFF (SEQ ID NO: 292), ESYKDRMYSF (SEQ ID NO: 293), KDRMYSF (SEQ ID NO: 294), YIPESYKDRMYSF (SEQ ID NO: 295), PESYKDRMYSFFR (SEQ ID NO: 296), YKDRMYSFFR (SEQ ID NO: 297), TRYFSMW (SEQ ID NO: 298), GDRTRYF (SEQ ID NO: 299), DSIGDRTRYF (SEQ ID NO: 300), DSIGDRTRYFSMW (SEQ ID NO: 301), GDRTRYFSMW (SEQ ID NO: 302), DRMYSFFRNF (SEQ ID NO: 303), SYKDRMYSFFRNF (SEQ ID NO: 304), NYNIGYQGFY (SEQ ID NO: 305), ANYNIGYQGF (SEQ ID NO: 306), MLANYNIGYQGFY (SEQ ID NO: 307), IGYQGFY (SEQ ID NO: 308), FLVQMLANYNIGY (SEQ ID NO: 309), NIGYQGF (SEQ ID NO: 310) and QMLANYNIGYQGF (SEQ ID NO: 311), , optionally wherein at most three, preferably at most two, most preferably at least one amino acid is independently substituted by any other amino acid.

Embodiment 32. The compound of any one of embodiments 1 to 30, wherein, independently for each occurrence, P comprises a 6- amino-acid fragment, preferably a 7-amino-acid-fragment, more preferably a 8-amino-acid-fragment, even more preferably a 9- amino-acid fragment, yet even more preferably a 10-amino-acid fragment, especially an entire sequence selected from the group of sequences consisting of YLQGPIW (SEQ ID NO: 312), VYLQGPI (SEQ ID NO: 313), WQNRDVY (SEQ ID NO: 314), DVYLQGP (SEQ ID NO: 315), QNRDVYL (SEQ ID NO: 316), LQGPIWA (SEQ ID NO: 317), RDVYLQG (SEQ ID NO: 318), NRDVYLQ (SEQ ID NO: 319), YFGYSTPWGYFDF (SEQ ID NO: 320), FGYSTPWGYF (SEQ ID NO: 321), GYSTPWGYFD (SEQ ID NO: 322), YSTPWGYFDF (SEQ ID NO: 323), NTYFGYSTPWGYF (SEQ ID NO: 324), TPWGYFDFNRFHC (SEQ ID NO: 325), TYFGYSTPWGYFD (SEQ ID NO: 326), DNTYFGYSTPWGY (SEQ ID NO: 327), YFGYSTPWGY (SEQ ID NO: 328), FGYSTPWGYFDFN (SEQ ID NO: 329), NWLPGPC (SEQ ID NO: 330), WLPGPCY (SEQ ID NO: 331), QAKNWLPGPC (SEQ ID NO: 332), AKNWLPGPCY (SEQ ID NO: 333), MANQAKNWLPGPC (SEQ ID NO: 334), QGCLPPF (SEQ ID NO: 335), GCLPPFP (SEQ ID NO: 336), VLGSAHQGCLPPF (SEQ ID NO: 337), LPYVLGSAHQGCL (SEQ ID NO: 338), YVLGSAHQGC (SEQ ID NO: 339), CLPPFPA (SEQ ID NO: 340), SAHQGCLPPF (SEQ ID NO: 341), VLGSAHQGCL (SEQ ID NO: 342), PYVLGSAHQGCLP (SEQ ID NO: 343), GRSSFYC (SEQ ID NO: 344), AVGRSSFYCLEYF (SEQ ID NO: 345), AVGRSSFYCL (SEQ ID NO: 346), QAVGRSSFYCLEY (SEQ ID NO: 347), NGSQAVGRSSFYC (SEQ ID NO: 348), DQYLYYL (SEQ ID NO: 349), PLIDQYLYYL (SEQ ID NO: 350), IDQYLYY (SEQ ID NO: 351), FFPSNGILIF (SEQ ID NO: 352), EERFFPSNGILIF

(SEQ ID NO: 353), VGSSSGNWHC (SEQ ID NO: 354) and ADGVGSSSGNWHC

(SEQ ID NO: 355), optionally wherein at most three, preferably at most two, most preferably at least one amino acid is independently substituted by any other amino acid; or wherein, independently for each occurrence, P comprises a 6-amino-acid fragment, preferably a 7-amino-acid-fragment, more preferably a 8-amino-acid-fragment, even more preferably a 9-amino-acid fragment, yet even more preferably a 10-amino-acid fragment or even a 11-amino-acid-fragment or yet even a 12-amino-acid- fragment, especially a 13-amino-acid-fragment selected from the group of sequences consisting of SEQ ID NOs: 383-1891 (see Table 1) - preferably group III of Table 1, more preferably group II of Table 1, especially group I of Table 1 - and SEQ ID NOs: 1892-2063 (see Table 2) - preferably group I of Table 2 - and sequences of group II or III of Table 3 (in particular SEQ ID NOs: 2064-2103), more preferably sequences of group I of Table 3, optionally wherein at most three, preferably at most two, most preferably at least one amino acid is independently substituted by any other amino acid; or wherein, independently for each occurrence, P comprises a 6-amino-acid fragment, preferably a 7-amino-acid-fragment, more preferably a 8-amino- acid-fragment, even more preferably a 9-amino-acid fragment, yet even more preferably a 10-amino-acid fragment or even a 11- amino-acid-fragment or yet even a 12-amino-acid-fragment, especially a 13-amino-acid-fragment selected from the group of sequences of Table 4, in particular the group of sequences identified by SEQ ID NOs: 2104-2190, optionally wherein at most three, preferably at most two, most preferably at least one amino acid is independently substituted by any other amino acid. Embodiment 33. The compound of any one of embodiments 1 to 32, wherein, independently for each occurrence, P consists of a 6- amino-acid fragment, preferably a 7-amino-acid-fragment, more preferably a 8-amino-acid-fragment, even more preferably a 9- amino-acid fragment, yet even more preferably a 10-amino-acid fragment, especially an entire sequence selected from the group of sequences set forth in embodiment 31 or selected from the group of sequences set forth in embodiment 32, optionally wherein at most three, preferably at most two, most preferably at least one amino acid is independently substituted by any other amino acid, optionally with an N-terminal and/or C- terminal cysteine residue.

Embodiment 34. The compound of any one of embodiments 1 to 33, wherein each of the peptide n-mers is covalently bound to the biopolymer scaffold, preferably via a linker each.

Embodiment 35. The compound of any one of embodiments 1 to 34, wherein at least one of said linkers is selected from disulphide bridges and PEG molecules.

Embodiment 36. The compound of any one of embodiments 1 to 35, wherein at least one of the spacers S is selected from PEG molecules or glycans.

Embodiment 37. The compound of any one of embodiments 1 to 36, wherein P _a comprises a 6-amino-acid fragment, preferably a 7- amino-acid-fragment, more preferably a 8-amino-acid-fragment, even more preferably a 9-amino-acid fragment, yet even more preferably a 10-amino-acid fragment, especially an entire sequence selected from the group of sequences set forth in embodiment 31, optionally wherein at most three, preferably at most two, most preferably at least one amino acid is independently substituted by any other amino acid.

Embodiment 38. The compound of any one of embodiments 1 to 37, wherein P _b comprises a 6-amino-acid fragment, preferably a 7- amino-acid-fragment, more preferably a 8-amino-acid-fragment, even more preferably a 9-amino-acid fragment, yet even more preferably a 10-amino-acid fragment, especially an entire sequence selected from the group of sequences set forth in embodiment 31, optionally wherein at most three, preferably at most two, most preferably at least one amino acid is independently substituted by any other amino acid.

Embodiment 39. The compound of any one of embodiments 1 to 36, wherein P _a comprises a 6-amino-acid fragment, preferably a 7- amino-acid-fragment, more preferably a 8-amino-acid-fragment, even more preferably a 9-amino-acid fragment, yet even more preferably a 10-amino-acid fragment, especially an entire sequence selected from the group of sequences set forth in embodiment 32, optionally wherein at most three, preferably at most two, most preferably at least one amino acid is independently substituted by any other amino acid.

Embodiment 40. The compound of any one of embodiments 1 to 37, wherein P _b comprises a 6-amino-acid fragment, preferably a 7- amino-acid-fragment, more preferably a 8-amino-acid-fragment, even more preferably a 9-amino-acid fragment, yet even more preferably a 10-amino-acid fragment, especially an entire sequence selected from the group of sequences set forth in embodiment 32, optionally wherein at most three, preferably at most two, most preferably at least one amino acid is independently substituted by any other amino acid.

Embodiment 41. The compound of any one of embodiments 6 to 40, wherein the first peptide n-mer is P _a - S - P _b and the second peptide n-mer is P _a - S - Pb.

Embodiment 42. The compound of any one of embodiments 6 to 41, wherein the peptide P _a and the peptide P _b comprise the same amino-acid sequence fragment, wherein the amino-acid sequence fragment has a length of at least 5 amino acids, even more preferably at least 6 amino acids, yet even more preferably at least 7 amino acids, especially at least 8 amino acids or even at least 9 amino acids.

Embodiment 43. The compound of any one of embodiments 1 to 42, wherein P _a consists of a 6-amino-acid fragment, preferably a 7- amino-acid-fragment, more preferably a 8-amino-acid-fragment, even more preferably a 9-amino-acid fragment, yet even more preferably a 10-amino-acid fragment, especially an entire sequence selected from the group of sequences set forth in embodiment 31, optionally wherein at most three, preferably at most two, most preferably at least one amino acid is independently substituted by any other amino acid, optionally with an N-terminal and/or C-terminal cysteine residue.

Embodiment 44. The compound of any one of embodiments 1 to 43, wherein P _b consists of a 6-amino-acid fragment, preferably a 7- amino-acid-fragment, more preferably a 8-amino-acid-fragment, even more preferably a 9-amino-acid fragment, yet even more preferably a 10-amino-acid fragment, especially an entire sequence selected from the group of sequences set forth in embodiment 31, optionally wherein at most three, preferably at most two, most preferably at least one amino acid is independently substituted by any other amino acid, optionally with an N-terminal and/or C-terminal cysteine residue.

Embodiment 45. The compound of any one of embodiments 1 to 42, wherein P _a consists of a 6-amino-acid fragment, preferably a 7- amino-acid-fragment, more preferably a 8-amino-acid-fragment, even more preferably a 9-amino-acid fragment, yet even more preferably a 10-amino-acid fragment, especially an entire sequence selected from the group of sequences set forth in embodiment 32, optionally wherein at most three, preferably at most two, most preferably at least one amino acid is independently substituted by any other amino acid, optionally with an N-terminal and/or C-terminal cysteine residue.

Embodiment 46. The compound of any one of embodiments 1 to 43, wherein P _b consists of a 6-amino-acid fragment, preferably a 7- amino-acid-fragment, more preferably a 8-amino-acid-fragment, even more preferably a 9-amino-acid fragment, yet even more preferably a 10-amino-acid fragment, especially an entire sequence selected from the group of sequences set forth in embodiment 32, optionally wherein at most three, preferably at most two, most preferably at least one amino acid is independently substituted by any other amino acid, optionally with an N-terminal and/or C-terminal cysteine residue

Embodiment 47. The compound of embodiments 1 to 46, wherein the first peptide n-mer is P _a - S - P _b and the second peptide n-mer iS P _a - S - Pb.

Embodiment 48. The compound of embodiments 1 to 47, wherein the peptide P _a and the peptide P _b comprise the same amino-acid sequence fragment, wherein the amino-acid sequence fragment has a length of at least 5 amino acids, even more preferably at least 6 amino acids, yet even more preferably at least 7 amino acids, especially at least 8 amino acids or even at least 9 amino acids.

Embodiment 49. The compound of any one of embodiments 1 to 48, wherein the viral vector is non-pathogenic (in the individual to be treated). Embodiment 50. The compound of any one of embodiments 1 to 49, wherein the biopolymer scaffold is an anti-CD163 antibody (i.e. an antibody specific for a CD163 protein) or GDI63-binding fragment thereof.

Embodiment 51. The compound of embodiment 50, wherein the anti- CD163 antibody or GDI63-binding fragment thereof is specific for human CD163 and/or is specific for the extracellular region of CD163, preferably for an SRCR domain of CD163, more preferably for any one of SRCR domains 1-9 of CD163, even more preferably for any one of SRCR domains 1-3 of CD163, especially for SRCR domain 1 of CD163.

Embodiment 52. The compound of embodiment 50 or 51, wherein the anti-CD163 antibody or GDI63-binding fragment thereof is specific for one of the following peptides: a peptide consisting of 7-25, preferably 8-20, even more preferably 9-15, especially 10-13 amino acids, wherein the peptide comprises the amino acid sequence CSGRVEVKVQEEWGTVCNNGWSMEA (SEQ ID NO: 3) or a 7-24 amino-acid fragment thereof, a peptide consisting of 7-25, preferably 8-20, even more preferably 9-15, especially 10-13 amino acids, wherein the peptide comprises the amino acid sequence DHVSCRGNESALWDCKHDGWG (SEQ ID NO: 13) or a 7-20 amino-acid fragment thereof, or a peptide consisting of 7-25, preferably 8-20, even more preferably 9-15, especially 10-13 amino acids, wherein the peptide comprises the amino acid sequence SSLGGTDKELRLVDGENKCS (SEQ ID NO: 24) or a 7-19 amino-acid fragment thereof.

Embodiment 53. The compound of embodiment 50 or 51, wherein the anti-CD163 antibody or CD163-binding fragment thereof is specific for a peptide comprising the amino acid sequence ESALW (SEQ ID NO: 14) or ALW.

Embodiment 54. The compound of embodiment 50 or 51, wherein the anti-CD163 antibody or GDI63-binding fragment thereof is specific for a peptide comprising the amino acid sequence GRVEVKVQEEW (SEQ ID NO: 4), WGTVCNNGWS (SEQ ID NO: 5) or WGTVCNNGW (SEQ ID NO: 6). Embodiment 55. The compound of embodiment 50 or 51, wherein the anti-CD163 antibody or GDI63-binding fragment thereof is specific for a peptide comprising the amino acid sequence SSLGGTDKELR (SEQ ID NO: 25) or SSLGG (SEQ ID NO: 26).

Embodiment 56. The compound of any one of embodiments 1 to 55, wherein the viral vector is AAV1, AAV2, AAV3, AAV5, AAV7 or AAV8.

Embodiment 57. The compound of any one of embodiments 1 to 55, wherein the viral vector is AAV8.

Embodiment 58. The compound of any one of embodiments 1 to 55, wherein the viral vector is Ad5.

Embodiment 59. The compound of any one of embodiments 58, wherein the viral vector is AdHu5.

Embodiment 60. The compound of any one of embodiments 1 to 59, wherein the viral vector is a viral vector specific for a mammal, in particular a human.

Embodiment 61. The compound of any one of embodiments 1 to 60, wherein the biopolymer scaffold is selected from human immunoglobulins and human transferrin.

Embodiment 62. The compound of embodiment any one of embodiments 1 to 61, wherein the biopolymer scaffold is human transferrin.

Embodiment 63. The compound of any one of embodiments 49 to 62, wherein at least one of the at least two peptides is circularized.

Embodiment 64. The compound of any one of embodiments 1 to 63, wherein the compound is non-immunogenic in humans.

Embodiment 65.A pharmaceutical composition comprising the compound of any one of embodiments 1 to 64 and at least one pharmaceutically acceptable excipient.

Embodiment 66. The pharmaceutical composition of embodiment 65, wherein the composition is prepared for intraperitoneal, subcutaneous, intramuscular and/or intravenous administration and/or wherein the composition is for repeated administration.

Embodiment 67. The pharmaceutical composition of any one of embodiments 1 to 66, wherein the molar ratio of peptide P to biopolymer scaffold in the composition is from 2:1 to 100:1, preferably from 3:1 to 90:1, more preferably from 4:1 to 80:1, even more preferably from 5:1 to 70:1, yet even more preferably from 6:1 to 60:1, especially from 7:1 to 50:1 or even from 8:10 to 40:1.

Embodiment 68. The pharmaceutical composition of any one of embodiments 6 to 67, wherein the molar ratio of peptide P _a to biopolymer scaffold in the composition is from 2:1 to 100:1, preferably from 3:1 to 90:1, more preferably from 4:1 to 80:1, even more preferably from 5:1 to 70:1, yet even more preferably from 6:1 to 60:1, especially from 7:1 to 50:1 or even from 8:10 to 40:1.

Embodiment 69. The pharmaceutical composition of any one of embodiments 6 to 68, wherein the molar ratio of peptide P _b to biopolymer scaffold in the composition is from 2:1 to 100:1, preferably from 3:1 to 90:1, more preferably from 4:1 to 80:1, even more preferably from 5:1 to 70:1, yet even more preferably from 6:1 to 60:1, especially from 7:1 to 50:1 or even from 8:10 to 40:1.

Embodiment 70. The pharmaceutical composition of any one of embodiments 65 to 69 for use in therapy.

Embodiment 71. The pharmaceutical composition for use according to embodiment 70, for use in increasing efficacy of a vaccine in an individual, wherein the vaccine comprises the viral vector, preferably wherein the pharmaceutical composition is administered to the individual prior to or concurrently with administration of the vaccine.

Embodiment 72. The pharmaceutical composition for use according to embodiment 71, wherein the pharmaceutical composition is administered at least twice within a 96-hour window, preferably within a 72-hour window, more preferably within a 48-hour window, even more preferably within a 36-hour window, yet even more preferably within a 24-hour window, especially within a 18- hour window or even within a 12-hour window; preferably wherein this window is followed by administration of the vaccine within 24 hours, preferably within 12 hours.

Embodiment 73. The pharmaceutical composition for use according to embodiment 70, for use in increasing efficacy of a gene therapy composition in an individual, wherein the gene therapy composition comprises the viral vector, preferably wherein the pharmaceutical composition is administered to the individual prior to or concurrently with administration of the gene therapy composition .

Embodiment 74. The pharmaceutical composition for use according to embodiment 73, wherein the pharmaceutical composition is administered at least twice within a 96-hour window, preferably within a 72-hour window, more preferably within a 48-hour window, even more preferably within a 36-hour window, yet even more preferably within a 24-hour window, especially within a 18- hour window or even within a 12-hour window; preferably wherein this window is followed by administration of the gene therapy composition within 24 hours, preferably within 12 hours.

Embodiment 75. The pharmaceutical composition for use according to any one of embodiments 71 to 74, wherein the individual is human.

Embodiment 76. The pharmaceutical composition for use according to any one of embodiments 70 to 75, wherein one or more antibodies are present in the individual which are specific for at least one occurrence of peptide P, or for peptide P _a and/or peptide Pb, preferably wherein said antibodies are neutralizing antibodies for said viral vector.

Embodiment 77. The pharmaceutical composition for use according to any one of embodiments 70 to 76, wherein the composition is non-immunogenic in the individual.

Embodiment 78. The pharmaceutical composition for use according to any one of embodiments 70 to 77, wherein the composition is administered at a dose of 1-1000 mg, preferably 2-500 mg, more preferably 3-250 mg, even more preferably 4-100 mg, especially 5-50 mg, compound per kg body weight of the individual.

Embodiment 79. The pharmaceutical composition for use according to any one of embodiments 70 to 78, wherein the composition is administered intraperitoneally, subcutaneously, intramuscularly or intravenously.

Embodiment 80.A method of sequestering (or depleting) one or more antibodies present in an individual, comprising obtaining a pharmaceutical composition as defined in any one of embodiments 65 to 69, wherein the composition is non- immunogenic in the individual and wherein the one or more antibodies present in the individual are specific for at least one occurrence of P, or for peptide P _a and/or peptide Pt; and administering the pharmaceutical composition to the individual .

Embodiment 81. The method of embodiment 80, wherein the individual is a non-human animal, preferably a non-human primate, a sheep, a pig, a dog or a rodent, in particular a mouse.

Embodiment 82. The method of embodiments 80 or 81, wherein the biopolymer scaffold is autologous with respect to the individual, preferably wherein the biopolymer scaffold is an autologous protein.

Embodiment 83. The method of any one of embodiments 80 to 82, wherein the individual is administered a vaccine or gene therapy composition comprising a viral vector prior to, concurrent with and/or subsequent to said administering of the pharmaceutical composition .

Embodiment 84. The method of any one of embodiments 80 to 83, wherein the individual is a non-human animal.

Embodiment 85. The method of any one of embodiments 80 to 82, wherein the individual is administered a vaccine or gene therapy composition comprising a viral vector and wherein the one or more antibodies present in the individual are specific for said viral vector, preferably wherein said administering of the vaccine or gene therapy composition is prior to, concurrent with and/or subsequent to said administering of the pharmaceutical composition .

Embodiment 86. The method of embodiment 85, wherein the viral vector contains genetic material.

Embodiment 87. The method of any one of embodiments 80 to 86, wherein the individual is healthy.

Embodiment 88. The method of any one of embodiments 80 to 87, wherein the composition is administered intraperitoneally, subcutaneously, intramuscularly or intravenously. Embodiment 89.A vaccine or gene therapy composition, comprising the compound of any one of embodiments 1 to 64 and further comprising the viral vector (typically wherein the viral vector contains genetic material) and optionally at least one pharmaceutically acceptable excipient; preferably wherein the viral vector comprises a peptide fragment with a sequence length of 6-13 amino acids, preferably 7-11 amino acids, more preferably 7-9 amino acids, and wherein the sequence of at least one occurrence of peptide P, or peptide P _a and/or peptide Pb, of the compound is at least 70% identical, preferably at least 75% identical, more preferably at least 80% identical, yet more preferably at least 85% identical, even more preferably at least 90% identical, yet even more preferably at least 95% identical, especially completely identical to the sequence of said peptide fragment.

Embodiment 90. The vaccine or gene therapy composition of embodiment 89, wherein the viral vector is AdV or AAV.

Embodiment 91. The vaccine of embodiment 89 or 90, wherein the vaccine further comprises an adjuvant.

Embodiment 92. The gene therapy composition of any one of embodiments 89 to 90, wherein the composition is prepared for intravenous administration.

Embodiment 93. The pharmaceutical composition of any one of embodiments 89 to 92, wherein the composition is an aqueous solution.

Embodiment 94. The pharmaceutical composition of any one of embodiments 89 to 93 for use in inhibition of an immune reaction, preferably an antibody-mediated immune reaction, against the active agent.

Embodiment 95. The pharmaceutical composition for use according to embodiment 94, wherein the composition is non-immunogenic in the individual.

Embodiment 96.A method of inhibiting an immune reaction to a treatment with an active agent in an individual in need of treatment with the active agent, comprising obtaining a pharmaceutical composition as defined in any one of embodiments 89 to 95; wherein the compound of the pharmaceutical composition is non-immunogenic in the individual, and administering the pharmaceutical composition to the individual .

Embodiment 97. The method of embodiment 96, wherein the individual is human.

Embodiment 98. The method of embodiment 96 or 97, wherein the biopolymer scaffold is autologous with respect to the individual, preferably wherein the biopolymer scaffold is an autologous protein.

Embodiment 99. The method of any one of embodiments 96 to 98, wherein the composition is administered intraperitoneally, subcutaneously, intramuscularly or intravenously.

Embodiment 100. A peptide with a sequence length of 6 to 50 amino acids, more preferably 6 to 25 amino acids, even more preferably 6 to 20 amino acids, yet more preferably 6 to 13 amino acids, wherein the peptide comprises a sequence of at least 4 or at least 5 or at least 6, preferably at least 7, more preferably at least 8, even more preferably at least 9, yet even more preferably at least 10 consecutive amino acids selected from: the group of AdV sequences ETGPPTVPFLTPPF (SEQ ID NO: 32), HDSKLSIATQGPL (SEQ ID NO: 33), LNLRLGQGPLFINSAHNLDINY (SEQ ID NO: 34), VDPMDEPTLLYVLFEVFDW (SEQ ID NO: 35), MKRARPSEDTFNPVYPYD (SEQ ID NO: 36), ISGTVQSAHLIIRFD (SEQ ID NO: 37), LGQGPLFINSAHNLDINYNKGLYLF (SEQ ID NO: 38), SYPFDAQNQLNLRLGQGPLFIN (SEQ ID NO: 39), GDTTPSAYSMSFSWDWSGHNYIN (SEQ ID NO: 40), VLLNNSFLDPEYWNFRN (SEQ ID NO: 41), HNYINEIFATSSYTFSYIA (SEQ ID NO: 42), DEAATALEINLEEEDDDNEDEVDEQAEQQKTH (SEQ ID NO: 43), INLEEEDDDNEDEVDEQAEQ (SEQ ID NO: 44), DNEDEVDEQAEQQKTHVF (SEQ ID NO: 45), EWDEAATALEINLEE (SEQ ID NO: 46), PKW LYSEDVDIETPDTHISYMP (SEQ ID NO: 47), YIPESYKDRMYSFFRNF (SEQ ID NO: 48), DSIGDRTRYFSMW (SEQ ID NO: 49), SYKDRMYSFFRNF (SEQ ID NO: 50), and FLVQMLANYNIGYQGFY (SEQ ID NO: 51), or the group of AAV sequences WQNRDVYLQGPIWAKIP (SEQ ID NO: 52), DNTYFGYSTPWGYFDFNRFHC (SEQ ID NO: 53), MANQAKNWLPGPCY (SEQ ID NO: 54), LPYVLGSAHQGCLPPFP (SEQ ID NO: 55), NGSQAVGRSSFYCLEYF (SEQ ID NO: 56), PLIDQYLYYL (SEQ ID NO: 57), EERFFPSNGILIF (SEQ ID NO: 58), ADGVGSSSGNWHC (SEQ ID NO: 59), SEQ ID NOs: 383-1891 (see Table 1) - preferably group III of Table 1, more preferably group II of Table 1, especially group I of Table 1 - and SEQ ID NOs: 1892-2063 (see Table 2) - preferably group I of Table 2 - and sequences of group II or III of Table 3 (in particular SEQ ID NOs: 2064-2103), more preferably sequences of group I of Table 3, or the group of sequences of Table 4, in particular the group of sequences identified by SEQ ID NOs: 2104-2190, optionally wherein at most three, preferably at most two, most preferably at least one amino acid of the sequence is independently substituted by any other amino acid; preferably wherein the peptide is a peptide as defined in embodiment 31, 32 or 33.

Embodiment 101. A method for detecting and/or quantifying AdV- or AAV-neutralizing antibodies in a biological sample comprising the steps of

- bringing the sample into contact with the peptide of embodiment 100, and

- detecting the presence and/or concentration of the antibodies in the sample.

Embodiment 102. The method of embodiment 101, wherein the peptide is immobilized on a solid support, in particular a biosensor-based diagnostic device with an electrochemical, fluorescent, magnetic, electronic, gravimetric or optical biotransducer and/or wherein the peptide is coupled to a reporter or reporter fragment, such as a reporter fragment suitable for a PGA.

Embodiment 103. The method of embodiment 101 or 102, wherein the method is a sandwich assay, preferably an enzyme-linked immunosorbent assay (ELISA).

Embodiment 104. The method of any one of embodiments 101 to 103, wherein the sample is obtained from a mammal, preferably a human. Embodiment 105. The method of any one of embodiment 101 to 104, wherein the sample is a blood sample, preferably whole blood, serum, or plasma.

Embodiment 106. Use of the peptide according to embodiment 100 in an enzyme-linked immunosorbent assay (ELISA), preferably for a method as defined in any one of embodiments 101 to 105.

Embodiment 107. Diagnostic device comprising the peptide according to embodiment 100 wherein the peptide is immobilized on a solid support and/or wherein the peptide is coupled to a reporter or reporter fragment, such as a reporter fragment suitable for a PCA.

Embodiment 108. Diagnostic device according to embodiment 107, wherein the solid support is an ELISA plate or a surface plasmon resonance chip.

Embodiment 109. Diagnostic device according to embodiment 107, wherein the diagnostic device is a lateral flow assay device or a biosensor-based diagnostic device with an electrochemical, fluorescent, magnetic, electronic, gravimetric or optical biotransducer.

Embodiment 110. A diagnostic kit comprising a peptide according to embodiment 100, preferably diagnostic device according to any one of embodiment 107 to 109, and preferably one or more selected from the group of a buffer, a reagent, instructions.

Embodiment 111. An apheresis device comprising the peptide according to embodiment 100, preferably immobilized on a solid carrier.

Embodiment 112. The apheresis device according to embodiment 111, wherein the solid carrier is capable of being contacted with blood or plasma flow.

Embodiment 113. The apheresis device according to embodiment 111 or 112, wherein the solid carrier comprises the compound according to any one of embodiments 1 to 64.

Embodiment 114. The apheresis device according to any one of embodiment 111 to 113, wherein the solid carrier is a sterile and pyrogen-free column. Embodiment 115. The apheresis device according to any one of embodiments 111 to 114, wherein the apheresis device comprises at least two, preferably at least three, more preferably at least four different peptides according to embodiment 100.

The present invention is further illustrated by the following figures and examples, without being restricted thereto. In the context of the following figures and examples the compound on which the inventive approach is based is also referred to as "Selective Antibody Depletion Compound" (SADC).

Fig. 1: SADCs successfully reduce the titre of undesired antibodies. Each SADC was applied at time point 0 by i.p. injection into Balb/c mice pre-immunized by peptide immunization against a defined antigen. Each top panel shows anti-peptide titers (0.5x dilution steps; X-axis shows log(X) dilutions) against CD values (y-axis) according to a standard ELISA detecting the corresponding antibody. Each bottom panel shows titers LogIC50 (y-axis) before injection of each SADC (i.e. titers at -48h and -24h) and after application of each SADC (i.e. titers +24h, +48h and +72h after injection; indicated on the x-axis). (A) Compound with albumin as the biopolymer scaffold that binds to antibodies directed against EBNA1 (associated with pre-eclampsia). The mice were pre-immunized with a peptide vaccine carrying the EBNA-1 model epitope. (B) Compound with albumin as the biopolymer scaffold that binds to antibodies directed against a peptide derived from the human AChR protein MIR (associated with myasthenia gravis). The mice were pre-immunized with a peptide vaccine carrying the AChR MIR model epitope. (C) Compound with immunoglobulin as the biopolymer scaffold that binds to antibodies directed against EBNA1 (associated with pre-eclampsia). The mice were preimmunized with a peptide vaccine carrying the EBNA-1 model epitope. (D) Compound with haptoglobin as the biopolymer scaffold that binds to antibodies directed against EBNA1 (associated with pre-eclampsia). The mice were pre-immunized with a peptide vaccine carrying the EBNA-1 model epitope. (E) Demonstration of selectivity using the same immunoglobulin-based SADC binding to antibodies directed against EBNA1 that was used in the experiment shown in panel C. The mice were pre-immunized with an unrelated amino acid sequence. No titre reduction occurred, demonstrating selectivity of the compound.

Fig. 2: SADCs are non-immunogenic and do not induce antibody formation after repeated injection into mice. Animals C1-C4 as well as animals C5-C8 were treated i.p. with two different SADCs. Control animal C was vaccinated with a KLH-peptide derived from the human AChR protein MIR. Using BSA-conjugated peptide probes T3-1, T9-1 and E005 (grey bars, as indicated in the graph), respectively, for antibody titer detection by standard ELISA at a dilution of 1:100, it could be demonstrated that antibody induction was absent in animals treated with an SADC, when compared to the vaccine-treated control animal C (y- axis, OD450 nm).

Fig. 3: Successful in vitro depletion of antibodies using SADCs carrying multiple copies of monovalent or divalent peptides. SADCs with mono- or divalent peptides were very suitable to adsorb antibodies and thereby deplete them. "Monovalent" means that peptide monomers are bound to the biopolymer scaffold (i.e. n=l) whereas "divalent" means that peptide dimers are bound to the biopolymer scaffold (i.e. n=2). In the present case, the divalent peptides were "homodivalent", i.e. the peptide n-mer of the SADC is E006 - spacer - E006).

Fig. 4: Rapid, selective antibody depletion in mice using various SADC biopolymer scaffolds. Treated groups exhibited rapid and pronounced antibody reduction already at 24hrs (in particular SADC-TF) when compared to the mock treated control group SADC-CTL (containing an unrelated peptide). SADC with albumin scaffold - SADC-ALB, SADC with immunoglobulin scaffold - SADC-IG, SADC with haptoglobin scaffold - SADC-HP, and SADC with transferrin scaffold - SADC-TF.

Fig. 5: Detection of SADCs in plasma via their peptide moieties 24hrs after SADC injection. Both haptoglobin-scaffold-based SADCs (SADC-HP and SADC-CTL) exhibited a relatively shorter plasma half life which represents an advantage over SADCs with other biopolymer scaffolds such as SADC-ALB, SADC-IG oder SADC- TF. SADC with albumin scaffold - SADC-ALB, SADC with immunoglobulin scaffold - SADC-IG, SADC with haptoglobin scaffold - SADC-HP, and SADC with transferrin scaffold - SADC- TF.

Fig. 6: Detection of SADC-IgG complexes in plasma 24hrs after SADC injection. Haptoglobin based SADCs were subject to accelerated clearance when compared to SADCs with other biopolymer scaffolds. SADC with albumin scaffold - SADC-ALB, SADC with immunoglobulin scaffold - SADC-IG, SADC with haptoglobin scaffold - SADC-HP, and SADC with transferrin scaffold - SADC-TF.

Fig. 7: In vitro analysis of SADC-IgG complex formation. Animals SADC-TF and -ALB showed pronounced immunocomplex formation and binding to Clq as reflected by the strong signals and by sharp signal lowering in case lOOOng/ml SADC-TF due to the transition from antigen-antibody equilibrium to antigen excess. In contrast, in vitro immunocomplex formation with SADC-HP or SADC- IG were much less efficient when measured in the present assay. These findings corroborate the finding that haptoglobin scaffolds are advantageous over other SADC biopolymer scaffolds because of the reduced propensity to activate the complement system. SADC with albumin scaffold - SADC-ALB, SADC with immunoglobulin scaffold - SADC-IG, SADC with haptoglobin scaffold - SADC-HP, and SADC with transferrin scaffold - SADC- TF.

Fig. 8: Determination of IgG capturing by SADCs in vitro. SADC- HP showed markedly less antibody binding capacity in vitro when compared to SADC-TF or SADC-ALB. SADC with albumin scaffold - SADC-ALB, SADC with immunoglobulin scaffold - SADC-IG, SADC with haptoglobin scaffold - SADC-HP, and SADC with transferrin scaffold - SADC-TF.

Fig. 9: Blood clearance of an anti-CD163-antibody-based biopolymer scaffold. In a mouse model, mAb E10B10 (specific for murine CD163) is much more rapidly cleared from circulation than mAb Mac2-158 (specific for human CD163 but not for murine CD163, thus serving as negative control in this experiment).

Fig. 10: AdV capsid protein sequences for use in the present invention. Databases accession numbers (in particular UniProt or GenBank accession numbers) are listed. Fig. 11: AAV capsid protein sequences for use in the present invention. Databases accession numbers (in particular UniProt or GenBank accession numbers are listed), as well as references to sequences in patent publications.

EXAMPLES

Examples 1-3, 5-8 and 11-13 demonstrate that SADCs are very well suited for selective removal of undesirable antibodies. Examples 4, 10 and 14-21 contain more details on the inventive compounds with respect to antibodies against viral vectors and corresponding peptide epitopes.

Example 1: SADCs effectively reduce the titre of undesired antibodies .

Animal models: In order to provide in vivo models with measurable titers of prototypic undesired antibodies in human indications, BALB/c mice were immunized using standard experimental vaccination with KLH-conjugated peptide vaccines derived from established human autoantigens or anti-drug antibodies. After titer evaluation by standard peptide ELISA, immunized animals were treated with the corresponding test SADCs to demonstrate selective antibody lowering by SADC treatment. All experiments were performed in compliance with the guidelines by the corresponding animal ethics authorities.

Immunization of mice with model antigens: Female BALB/c mice (aged 8-10 weeks) were supplied by Janvier (France), maintained under a 12h light/12h dark cycle and given free access to food and water. Immunizations were performed by s.c. application of KLH carrier-conjugated peptide vaccines injected 3 times in biweekly intervals. KLH conjugates were generated with peptide T3-2 (SEQ ID NO. 356: CGRPQKRPSCIGCKG), which represents an example for molecular mimicry between a viral antigen (EBNA-1) and an endogenous human receptor antigen, namely the placental GPR50 protein, that was shown to be relevant to preeclampsia (Elliott et al.). In order to confirm the generality of this approach, a larger antigenic peptide derived from the autoimmune condition myasthenia gravis was used for immunization of mice with a human autoepitope. In analogy to peptide T3-2, animals were immunized with peptide Tl-1 (SEQ ID NO. 357: LKWNPDDYGGVKKIHIPSEKGC) , derived from the MIR (main immunogenic region) of the human AChR protein which plays a fundamental role in pathogenesis of the disease (Luo et al.). The Tl-1 peptide was used for immunizing mice with a surrogate partial model epitope of the human AChR autoantigen. The peptide T8-1 (SEQ ID NO. 358: DHTLYTPYHTHPG) was used to immunize control mice to provide a control titer for proof of selectivity of the system. For vaccine conjugate preparation, KLH carrier (Sigma) was activated with sulfo-GMBS (Cat. Nr. 22324 Thermo), according to the manufacturer's instructions, followed by addition of either N- or C-terminally cysteinylated peptides T3-2 and Tl-1 and final addition of Alhydrogel® before injection into the flank of the animals. The doses for vaccines T3-2 and Tl-1 were 15μg of conjugate in a volume of lOOul per injection containing Alhydrogel® (InvivoGen VAC-Alu-250) at a final concentration of 1% per dose.

Generation of prototypic SADCs: For testing selective antibody lowering activity by SADCs of T3-2 and Tl-1 immunized mice, SADCs were prepared with mouse serum albumin (MSA) or mouse immunoglobulin (mouse-Ig) as biopolymer scaffold in order to provide an autologous biopolymer scaffold, that will not induce any immune reaction in mice, or non-autologuous human haptoglobin as biopolymer scaffold (that did not induce an allogenic reaction after one-time injection within 72 hours). N- terminally cysteinylated SADC peptide E049 (SEQ ID NO. 359: GRPQKRPSCIG) and/or C-terminally cysteinylated SADC peptide E006 (SEQ ID NO. 360: VKKIHIPSEKG) were linked to the scaffold using sulfo-GMBS (Cat. Nr. 22324 Thermo)-activated MSA (Sigma; Cat. Nr. A3559) or -mouse-Ig (Sigma, 15381) or -human haptoglobin (Sigma H0138) according to the instructions of the manufacturer, thereby providing MSA-, Ig- and haptoglobin-based SADCs with the corresponding cysteinylated peptides, that were covalently attached to the lysines of the corresponding biopolymer scaffold. Beside conjugation of the cysteinylated peptides to the lysines via a bifunctional amine-to-sulfhydryl crosslinker, a portion of the added cysteinylated SADC peptides directly reacted with sulfhydryl groups of cysteins of the albumin scaffold protein, which can be detected by treating the conjugates with DTT followed by subsequent detection of free peptides using mass spectrometry or any other analytical method that detects free peptide. Finally, these SADC conjugates were dialysed against water using Pur-A-Lyzer™ (Sigma) and subsequently lyophilized. The lyophilized material was resuspended in PBS before injection into animals.

In vivo functional testing of SADCs: Prototypic SADCs, SADC- E049 and SADC-E006 were injected intraperitoneally (i.p.; as a surrogate for an intended intravenous application in humans and larger animals) into the mice that had previously been immunized with peptide vaccine T3-2 (carrying the EBNA-1 model epitope) and peptide vaccine Tl-1 (carrying the AChR MIR model epitope). The applied dose was 30μg SADC conjugate in a volume of 50pl PBS. Blood takes were performed by submandibular vein puncture, before (-48h, -24h) and after (+24h,+48h,+72h, etc.) i.p. SADC injections, respectively, using capillary micro-hematocrit tubes. Using ELISA analysis (see below), it was found that both prototypic SADCs were able to clearly reduce the titers over a period of at least 72 hrs in the present animal model. It could therefore be concluded that SADCs can be used to effectively reduce titers in vivo.

Titer analysis: Peptide ELISAs were performed according to standard procedures using 96-well plates (Nunc Medisorp plates; Thermofisher, Cat Nr 467320) coated for Ih at RT with BSA- coupled peptides (30nM, dissolved in PBS) and incubated with the appropriate buffers while shaking (blocking buffer, 1% BSA, lx PBS; washing buffer, IxPBS / 0,1% Tween; dilution buffer, IxPBS / 0.1% BSA /0,l% Tween). After serum incubation (dilutions starting at 1:50 in PBS; typically in 1:3 or 1:2 titration steps), bound antibodies were detected using Horseradish Peroxidase-conjugated goat anti-mouse IgG (Fc) from Jackson immunoresearch (115-035-008). After stopping the reaction, plates were measured at 450nm for 20min using TMB. EC50 were calculated from readout values using curve fitting with a 4- parameter logistic regression model (GraphPad Prism) according to the procedures recommended by the manufacturer. Constraining parameters for ceiling and floor values were set accordingly, providing curve fitting quality levels of R ² >0.98.

Figure 1A shows an in vivo proof of concept in a mouse model for in vivo selective plasma-lowering activity of a prototypic albumin-based SADC candidate that binds to antibodies directed against EBNA1, as a model for autoantibodies and mimicry in preeclampsia (Elliott et al.). For these mouse experiments, mouse albumin was used, in order to avoid any reactivity against a protein from a foreign species. Antibody titers were induced in 6 months old Balb/c mice by standard peptide vaccination. The bottom panel demonstrates that titers LogIC50 (y-axis) before SADC injection (i.e. titers at -48h and -24h) were higher than titers LogIC50 after SADC application (i.e. titers +24h, +48h and +72h after injection; indicated on the x-axis).

A similar example is shown in Figure IB, using an alternative example of a peptidic antibody binding moiety for a different disease indication. Antibody lowering activity of an albumin-based SADC in a mouse model that was pre-immunized with a different peptide derived from the human AChR protein MIR region (Luo et al.) in order to mimic the situation in myasthenia gravis. The induced antibody titers against the AChR- MIR region were used as surrogate for anti-AChR-MIR autoantibodies known to play a causative role in myasthenia gravis (reviewed by Vincent et al.). A clear titer reduction was seen after SADC application.

Figures 1C and ID demonstrate the functionality of SADC variants comprising alternative biopolymer scaffolds. Specifically, Figure 1C shows that an immunoglobulin scaffold can be successfully used whereas Figure ID demonstrates the use of a haptoglobin-scaffold for constructing an SADC. Both examples show an in vivo proof of concept for selective antibody lowering by an SADC, carrying covalently bound example peptide E049.

The haptoglobin-based SADC was generated using human Haptoglobin as a surrogate although the autologuous scaffold protein would be preferred. In order to avoid formation of antihuman-haptoglobin antibodies, only one single SADC injection per mouse of the non-autologuous scaffold haptoglobin was used for the present experimental conditions. As expected, under the present experimental conditions (i.e. one-time application), no antibody reactivity was observed against the present surrogate haptoglobin homologue.

Figure IE demonstrates the selectivity of the SADC system. The immunoglobulin-based SADC carrying the peptide E049 (i.e. the same as in Figure 1C) cannot reduce the Ig-titer that was induced by a peptide vaccine with an unrelated, irrelevant amino acid sequence, designated peptide T8-1 (SEQ ID NO. 358: DHTLYTPYHTHPG) . The example shows an in vivo proof of concept for the selectivity of the system. The top panel shows antipeptide T8-1 titers (0,5x dilution steps starting from 1:50 to 1:102400; X-axis shows log(X) dilutions) against OD values (y- axis) according to a standard ELISA. T8-l-titers are unaffected by administration of SADC-Ig-E049 after application. The bottom panel demonstrates that the initial titers LogIC50 (y-axis) before SADC injection (i.e. titers at -48h and -24h) are unaffected by administration of SADC-Ig-E049 (arrow) when compared to the titers LogIC50 after SADC application (i.e. titers +24h, +48h and +72h; as indicated on the x-axis), thereby demonstrating the selectivity of the system.

Example 2: Immunogenicity of SADCs.

In order to exclude immunogenicity of SADCs, prototypic candidate SADCs were tested for their propensity to induce antibodies upon repeated injection. Peptides T3-1 and T9-1 were used for this test. T3-1 is a 10-amino acid peptide derived from a reference epitope of the Angiotensin receptor, against which agonistic autoantibodies are formed in a pre-eclampsia animal model (Zhou et al.); T9-1 is a 12-amino acid peptide derived from a reference anti-drug antibody epitope of human IFN gamma (Lin et al.). These control SADC conjugates were injected 8 x every two weeks i.p. into naive, non-immunized female BALB/c mice starting at an age of 8-10 weeks.

Animals C1-C4 were treated i.p. (as described in example 1) with SADC T3-1. Animals C5-C8 were treated i.p. with an SADC carrying the peptide T9-1. As a reference signal for ELISA analysis, plasma from a control animal that was vaccinated 3 times with KLH-peptide Tl-1 (derived from the AChR-MIR, explained in Example 1) was used. Using BSA-conjugated peptide probes T3-1, T9-1 and E005 (SEQ ID NO. 361: GGVKKIHIPSEK), respectively, for antibody titer detection by standard ELISA at a dilution of 1:100, it could be demonstrated that antibody induction was absent in SADC-treated animals, when compared to the vaccine-treated control animal C (see Figure 2). The plasmas were obtained by submandibular blood collection, 1 week after the 3rd vaccine injection (control animal C) and after the last of 8 consecutive SADC injections in 2-weeks intervals (animals C1-C8), respectively. Thus it was demonstrated that SADCs are non-immunogenic and do not induce antibody formation after repeated injection into mice.

Example 3: Successful in vitro depletion of antibodies using SADCs carrying multiple copies of monovalent or divalent peptides.

Plasma of E006-KLH (VKKIHIPSEKG (SEQ ID NO: 360) with C- terminal cysteine, conjugated to KLH) vaccinated mice was diluted 1:3200 in dilution buffer (PBS + 0.1% w/v BSA + 0.1% Tween20) and incubated (100 pl, room temperature) sequentially (10 min/well) four times on single wells of a microtiter plate that was coated with 2.5 μg/ml (250 ng/well) of SADC or 5 μg/ml (500 ng/well) albumin as negative control.

In order to determine the amount of free, unbound antibody present before and after incubation on SADC coated wells, 50 pl of the diluted serum were taken before and after the depletion and quantified by standard ELISA using E006-BSA coated plates (10 nM peptide) and detection by goat anti mouse IgG bio (Southern Biotech, diluted 1:2000). Subsequently, the biotinylated antibody was detected with Streptavidin-HRP (Thermo Scientific, diluted 1:5000) using TMB as substrate. Development of the signal was stopped with 0.5 M sulfuric acid.

ELISA was measured at OD450nm (y-axis). As a result, the antibody was efficiently adsorbed by either coated mono- or divalent SADCs containing peptide E006 with C-terminal cysteine (sequence VKKIHIPSEKGC, SEQ ID NO: 362) (before=non-depleted starting material; mono- divalent corresponds to peptides displayed on the SADC surface; neg. control was albumin; indicated on the x-axis). See Fig. 3. ("Monovalent" means that peptide monomers are bound to the biopolymer scaffold (i.e. n=l) whereas "divalent" means that peptide dimers are bound to the biopolymer scaffold (i.e. n=2). In the present case, the divalent peptides were "homodivalent", i.e. the peptide n-mer of the SADC is E006 - S - E006.) This demonstrates that SADCs with mono- or divalent peptides are very suitable to adsorb antibodies and thereby deplete them.

Example 4: Generation of mimotope-based SADCs mAb 4D2 is a mouse IgG2a mAb targeting the adenovirus fiber epitope peptide (NCBI Reference Sequence: AP_000226.1). It represents a prototype neutralizing antibody that was generated from UV irradiated Ad2 virus (Krasnykh et al, 1998).

Linear and circular peptides derived from wild-type or modified peptide amino acid sequences can be used for the construction of specific SADCs for the selective removal of neutralizing antibodies against viral vectors. In case of a particular epitope, linear peptides or constrained peptides such as cyclopeptides containing portions of an epitope or variants thereof, where for example, one or several amino acids have been substituted or chemically modified in order to improve affinity to an antibody (mimotopes), can be used for constructing SADCs. A peptide screen can be performed with the aim of identifying peptides with optimized affinity to neutralizing antibodies. The flexibility of structural or chemical peptide modification provided a solution to minimize the risk of immunogenicity, in particular of binding of the peptide to HLA and thus the risk of unwanted immune stimulation.

Therefore, wild-type as well as modified linear and circular peptide sequences are derived from an epitope of a viral capsid protein as disclosed herein, e.g. the epitopic sequence LNLRLGQGPLFINSAHNLDINY (SEQ ID NO: 34) of mAh 4D2 found in the course of the present invention (see example further below). Peptides of various length and positions are systematically permutated by amino acid substitutions and synthesized on a peptide array. This allows screening of 60000 circular and linear wild-type and mimotope peptides derived from these sequences. The peptide arrays are incubated with mAb 4D2. This antibody is therefore used to screen the 60000 peptides and 100 circular and 100 linear peptide hits are selected based on their relative binding strength to the antibody. Of these 200 peptides, 51 sequences are identical between the circular and the linear peptide group. All of the best peptides identified have at least one amino acid substitution when aligned to the original sequences, respectively and are therefore regarded as mimotopes. Also, higher binding strengths can be achieved with circularized peptides.

These newly identified peptides, preferentially those with high relative binding values, are used to generate SADCs for increasing efficacy of AdV-based vector vaccines.

Example 5: Rapid, selective antibody depletion in mice using various SADC biopolymer scaffolds.

10 μg of model undesired antibody mAb anti V5 (Thermo Scientific) was injected i.p. into female Balb/c mice (5 animals per treatment group; aged 9-11 weeks) followed by intravenous injection of 50 μg SADC (different biopolymer scaffolds with tagged V5 peptides bound, see below) 48hrs after the initial antibody administration. Blood was collected at 24hrs intervals from the submandibular vein. Blood samples for time point 0 hrs were taken just before SADC administration.

Blood was collected every 24 hrs until time point 120 hrs after the SADC administration (x-axis). The decay and reduction of plasma anti-V5 IgG levels after SADC administration was determined by anti V5 titer readout using standard ELISA procedures in combination with coated V5-peptide-BSA (peptide sequence IPNPLLGLDC - SEQ ID NO: 561) and detection by goat anti mouse IgG bio (Southern Biotech, diluted 1:2000) as shown in Fig. 4. In addition, SADC levels (see Example 6) and immunocomplex formation (see Example 7) were analyzed.

EC50[OD450] values were determined using 4 parameter logistic curve fitting and relative signal decay between the initial level (set to 1 at time point 0) and the following time points (x-axis) was calculated as ratio of the EC50 values (y- axis, fold signal reduction EC50). All SADC peptides contained tags for direct detection of SADC and immunocomplexes from plasma samples; peptide sequences used for SADCs were: IPNPLLGLDGGSGDYKDDDDKGK (SEQ ID NO: 363)- (BiotinAca)GC (SADC with albumin scaffold - SADC-ALB, SADC with immunoglobulin scaffold - SADC-IG, SADC with haptoglobin scaffold - SADC-HP, and SADC with transferrin scaffold - SADC-TF) and unrelated peptide VKKIHIPSEKGGSGDYKDDDDKGK (SEQ ID NO: 364)- (BiotinAca)GC as negative control SADC (SADC-CTR).

The SADC scaffolds for the different treatment groups of 5 animals are displayed in black/grey shades (see inset of Fig. 4).

Treated groups exhibited rapid and pronounced antibody reduction already at 24hrs (in particular SADC-TF) when compared to the mock treated control group SADC-CTL. SADC-CTR was used as reference for a normal antibody decay since it has no antibody lowering activity because its peptide sequence is not recognized by the administered anti V5 antibody. The decay of SADC-CTR is thus marked with a trend line, emphasizing the antibody level differences between treated and mock treated animals.

In order to determine the effectivity of selective antibody lowering under these experimental conditions, a two-way ANOVA test was performed using a Dunnett's multiple comparison test. 48 hrs after SADC administration, the antibody EC50 was highly significantly reduced in all SADC groups (p<0.0001) compared to the SADC-CTR reference group (trend line). At 120 hrs after SADC administration, antibody decrease was highly significant in the SADC-ALB and SADC-TF groups (both p<0.0001) and significant in the SADC-HP group (p=0.0292), whereas the SADC-IG group showed a trend towards an EC50 reduction (p = 0.0722) 120 hrs after SADC administration. Of note, selective antibody reduction was highly significant (p<0.0001) in the SADC-ALB and SADC-TF groups at all tested time-points after SADC administration.

It is concluded that all SADC biopolymer scaffolds were able to selectively reduce antibody levels. Titer reduction was most pronounced with SADC-ALB and SADC-TF and no rebound or recycling of antibody levels was detected towards the last time points suggesting that undesired antibodies are degraded as intended.

Example 6: Detection of SADCs in plasma 24hrs after SADC injection.

Plasma levels of different SADC variants at 24hrs after i.v. injection into Balb/c mice. Determination of Plasma levels (y- axis) of SADC-ALB, -IG, -HP, -TF and the negative control SADC- CTR (x-axis), were detected in the plasmas from the animals already described in example 5. Injected plasma SADC levels were detected by standard ELISA whereby SADCs were captured via their biotin moieties of their peptides in combination with streptavidin coated plates (Thermo Scientific). Captured SADCs were detected by mouse anti Flag-HRP antibody (Thermo Scientific, 1:2,000 diluted) detecting the Flag-tagged peptides (see also example 7):

Assuming a theoretical amount in the order of 25 μg/ml in blood after injecting 50 μg SADC i.v., the detectable amount of SADC ranged between 799 and 623 ng/ml for SADC-ALB or SADC-IG and up to approximately 5000 ng/ml for SADC-TF, 24 hrs after SADC injection. However surprisingly and in contrast, SADC-HP and control SADC-CTR (which is also a SADC-HP variant, however carrying the in this case unrelated negative control peptide E006, see previous examples), had completely disappeared from circulation 24hrs after injection, and were not detectable anymore. See Fig. 5.

This demonstrates that both Haptoglobin scaffold-based SADCs tested in the present example ((namely SADC-HP and SADC-CTR) exhibit a relatively shorter plasma half-life which represents an advantage over SADCs such as SADC-ALB, SADC-IG oder SADC-TF in regard of their potential role in complement-dependent vascular and renal damage due to the in vivo risk of immunocomplex formation. Another advantage of SADC-HP is the accelerated clearance rate of their unwanted target antibody from blood in cases where a rapid therapeutic effect is needed. The present results demonstrate that Haptoglobin-based SADC scaffolds (as represented by SADC-HP and SADC-CTR) are subject to rapid clearance from the blood, regardless of whether SADC- binding antibodies are present in the blood, thereby minimizing undesirable immunocomplex formation and showing rapid and efficient clearance. Haptoglobin-based SADCs such as SADC-HP in the present example thus provide a therapeutically relevant advantage over other SADC biopolymer scaffolds, such as demonstrated by SADC-TF or SADC-ALB, both of which are still detectable 24hrs after injection under the described conditions, in contrast to SADC-HP or SADC-CTR which both are completely cleared 24hrs after injection. Example 7: Detection of SADC-IgG complexes in plasma 24hrs after SADC injection.

In order to determine the amount IgG bound to SADCs in vivo, after i.v. injection of 10 gg anti V5 IgG (Thermo Scientific) followed by injection of SADC-ALB, -HP, -TF and -CTR (50 gg) administered i.v. 48h after antibody injection, plasma was collected from the submandibular vein, 24hrs after SADC injection, and incubated on streptavidin plates for capturing SADCs from plasma via their biotinylated SADC-V5-peptide [IPNPLLGLDGGSGDYKDDDDKGK (SEQ ID NO: 363)(BiotinAca)GC or in case of SADC-CTR the negative control peptide VKKIHIPSEKGGSGDYKDDDDKGK (SEQ ID NO: 364)(BiotinAca)GC]. IgG bound to the streptavidin-captured SADCs was detected by ELISA using a goat anti mouse IgG HRP antibody (Jackson Immuno Research, diluted 1:2,000) for detection of the SADC-antibody complexes present in plasma 24hrs after SADC injection. OD450nm values (y-axis) obtained for a negative control serum from untreated animals were subtracted from the OD450nm values of the test groups (x-axis) for background correction.

As shown in Fig. 6, pronounced anti-V5 antibody signals were seen in case of SADC-ALB and SADC-TF injected mice (black bars represent background corrected OD values at a dilution of 1:25 , mean value of 5 mice; standard deviation error bars), whereas no antibody signal could be detected in plasmas from SADC-HP or control SADC-CTR injected animals (SADC-CTR is a negative control carrying the irrelevant peptide bio-FLG-E006 [VKKIHIPSEKGGSGDYKDDDDKGK (SEQ ID NO: 364)(BiotinAca)GC] that is not recognized by any anti V5 antibody). This demonstrates the absence of detectable amounts of SADC-HP/IgG complexes in the plasma 24hrs after i.v. SADC application.

SADC-HP is therefore subject to accelerated clearance in anti V5 pre-injected mice when compared to SADC-ALB or SADC-TF.

Example 8: In vitro analysis of SADC-immunoglobulin complex formation

SADC-antibody complex formation was analyzed by preincubating 1 gg/ml of human anti V5 antibody (anti V5 epitope tag [SV5-P-K], human IgG3, Absolute Antibody) with increasing concentrations of SADC-ALB, -IG, -HP, -TF and -CTR (displayed on the x-axis) in PBS +0.1% w/v BSA + 0.1% v/v Tween20 for 2 hours at room temperature in order to allow for immunocomplex formation in vitro. After complex formation, samples were incubated on ELISA plates that had previously been coated with 10 μg/ml of human Gig (CompTech) for 1 h at room temperature, in order to allow capturing of in vitro formed immunocomplexes. Complexes were subsequently detected by ELISA using anti human IgG (Fab specific)-Peroxidase (Sigma, diluted 1:1,000). Measured signals at OD450 nm (y-axis) reflect Antibody-SADC complex formation in vitro.

As shown in Fig. 7, SADC-TF and -ALB showed pronounced immunocomplex formation and binding to Clq as reflected by the strong signals and by sharp signal lowering in case lOOOng/ml SADC-TF due to the transition from antigen-antibody equilibrium to antigen excess. In contrast, in vitro immunocomplex formation with SADC-HP or SADC-IG were much less efficient when measured in the present assay.

Together with the in vivo data (previous examples), these findings corroborate the finding that haptoglobin scaffolds are advantageous over other SADC biopolymer scaffolds because of the reduced propensity to activate the complement system. In contrast, SADC-TF or SADC-ALB show higher complexation, and thereby carry a certain risk of activating the Cl complex with initiation of the classical complement pathway (a risk which may be tolerable in some settings, however).

Example 9: Determination of IgG capturing by SADCs in vitro

Immunocomplexes were allowed to form in vitro, similar to the previous example, using 1 μg/ml mouse anti V5 antibody (Thermo Scientific) in combination with increasing amounts of SADCs (displayed on the x-axis). SADC-antibody complexes were captured on a streptavidin coated ELISA plate via the biotinylated SADC-peptides (see previous examples), followed by detection of bound anti-V5 using anti mouse IgG-HRP (Jackson Immuno Research, diluted 1:2,000).

Under these assay conditions, SADC-HP showed markedly less antibody binding capacity in vitro when compared to SADC-TF or SADC-ALB (see Fig. 8, A). The calculated EC50 values for IgG detection on SADCs were 7.0 ng/ml, 27.9 ng/ml and 55.5 ng/ml for SADC-TF, -ALB and -HP, respectively (see Fig. 8, B).

This in vitro finding is consistent with the observation (see previous examples) that SADC-HP has a lower immunocomplex formation capacity when compared to SADC-TF or SADC-ALB which is regarded as a safety advantage with respect to its therapeutic use for the depletion of unwanted antibodies.

Example 10: SADCs to reduce undesired antibodies against AAV-8

Three SADCs are provided to reduce AAV-8-neutralizing antibodies which hamper gene therapy (see Gurda et al. for the epitopes used; see also AAV-8 capsid protein sequence UniProt Q8JQF8, sequence version 1):

(a) SADC-a with Mac2-158 (as disclosed in WO 2011/039510

A2) as biopolymer scaffold and at least two peptides with the sequence YLQGPIW (SEQ ID NO: 312) covalently bound to the scaffold,

(b) SADC-b with human transferrin as biopolymer scaffold and at least two peptides with the sequence YFGYSTPWGYFDF (SEQ ID NO: 320) covalently bound to the scaffold, and

(c) SADC-c with human albumin as biopolymer scaffold and at least two peptides with the sequence QGCLPPF (SEQ ID NO: 335) covalently bound to the scaffold.

These SADCs are administered to an individual who will undergo gene therapy with AAV-8 as vector in order to increase efficiency of the gene therapy.

Example 11: In-vivo function of anti-CD163-antibodY-based SADC biopolymer scaffold

Rapid in vivo blood clearance of anti-mouse-CDl63 mAb E10B10 (as disclosed in WO 2011/039510 A2). mAb E10B10 was resynthesized with a mouse IgG2a backbone. 50 μg mAb E10B10 and Mac2-158 (human-specific anti-CD163 mAb as disclosed in WO 2011/039510 A2, used as negative control in this example since it does not bind to mouse CD163) were injected i.v. into mice and measured after 12, 24, 36, 48 , 72, 96 hours in an ELISA to determine the blood clearance. mAb E10B10 was much more rapidly cleared from circulation than control mAb Mac2-158 was, as shown in Fig. 9, since E10B10 binds to the mouse CD163 whereas Mac2-158 is human-specific, although both were expressed as mouse IgG2a isotypes for direct comparison.

In conclusion, anti-CD163 antibodies are highly suitable as SADC scaffold because of their clearance profile. SADCs with such scaffolds will rapidly clear undesirable antibodies from circulation.

Detailed methods: 50 ug of biotinylated monoclonal antibodies E10B10 and biotinylated Mac2-158 were injected i.v. into mice and measured after 12, 24, 36, 48, 72, 96 hours to determine the clearance by ELISA: Streptavidin plates were incubated with plasma samples diluted in PBS + 0.11BSA + 0.1% Tween20 for 1 h at room temperature (50 pl/well). After washing (3x with PBS + 0.1% Tween20), bound biotinylated antibodies were detected with anti-mouse IgG+IgM-HRP antibody at a 1:1000 dilution. After washing, TMB substrate was added and development of the substrate was stopped with TMB Stop Solution. The signal at OD450 nm was read. The EC50 values were calculated by nonlinear regression using 4 parametric curve fitting with constrained curves and least squares regression. EC50 values at time-point T12 (this was the first measured time-point after antibody injection) was set at 100%, all other EC50 values were compared to the levels at T12.

Example 12: Epitope mapping of anti-CD163 mAbs mAb E10B10 provides GDI63-mediated, accelerated in vivo clearance from blood in mice (see example 11). The epitope of this antibody was fine mapped using circular peptide arrays, whereby the peptides were derived from mouse CD163. As a result, a peptide cluster that is recognized by mAb E10B10 was identified (see example 13).

The same epitope mapping procedure using circularized peptides was performed with mAb Mac2-158 (as disclosed in WO 2011/039510 A2). Epitope mapping results for mAb Mac2-158 yielded two peptide clusters (see example 13) which allowed further demarcation of CD163 epitope regions that are especially relevant to internalization of ligands and antibodies that bind to the receptor.

These newly characterized epitopes for Mac2-158 and E10B10 thus revealed three preferred binding regions for antibodies against CD163. Based on the fine epitope mapping work, linear or preferentially circular peptides are synthesized and used for the induction, production and selection of polyclonal or monoclonal antibodies or other GDI63-binding SADC scaffolds that target CD163.

Example 13: Epitope mapping of anti-CD163 mAbs

Peptides aligned to SRCR domain 1 of human GDI63 were selected from the top 20 peptide hits of mAh Mac2-158 circular epitope mapping peptides and the most preferred sequences were selected from two peptide alignment clusters at the N-terminus and at the C-terminus of SRCR-1 of human CD163. As a result, the following sequences (as well as motifs derived therefrom) are highly suitable epitopes anti-CD163 antibodies and fragments thereof used as SADC biopolymer scaffold:

Fine epitope mapping of mAb E10B10 was performed as for Mac2-158. 1068 circular peptides (sized 7, 10 and 13 amino acids) and derived from SRCR-1 to -3 of the mouse CD163 sequence (UniProKB Q2VLH6.2) were screened with mAb E10B10 and the following top binding peptides were obtained (ranked by relative signal strength). The human CD163 sequence was aligned to this cluster of mouse CD163 sequences, revealing another highly suitable epitope: Peptide cluster 3:

The human homologues of mouse peptides 01 - 13 from cluster 3 have the following sequences of the N-terminal portion of the mature human CD163 protein (UniProtKB: Q86VB7):

These homologue peptides represent further highly suitable epitopes for the anti-CD163 antibody-based biopolymer scaffold.

Example 14: Epitope mapping of mAb 4D2 against AdV mAb 4D2 is a mouse IgG2a mAb targeting the adenovirus fiber epitope peptide (NCBI Reference Sequence: AP_000226.1). It represents a prototype neutralizing antibody that was generated from UV irradiated Ad2 virus (Krasnykh et al, 1998). In order to obtain cyclic antibody binding peptides from the virus neutralizing epitope, mAb 4D2 was mapped against aligned cyclic peptides derived from the fiber sequence. The sequence at amino acid positions 1 to 581 of NCBI Reference Sequence: AP_000226.1 was used as a starting sequence for designing 7mer, lOmer and 13mer cyclic peptides that were then synthesized and circularized directly on a peptide microarray and subsequently incubated with various concentrations of the antibody. The binding signal of monoclonal antibody 4D2 to the peptides yielded several binding hits that were be aligned against the sequence of the protein and subsequently clustered. The resulting clusters were designated clusterl (length=14 amino acids), cluster! (length=13 amino acids) and clusters (length=22 amino acids). Below are the aligments of the corresponding new peptides that are able to bind the mAb 4D2 paratope. The number of the peptide names corresponds to the rank of the binding signal of the antibody to the microarray (i.e. peptide 01 binds strongest, 02 second strongest, etc.). A selection of top candidate binding peptides out of the top 50 top binders was aligned against the corresponding protein sequence (first line).

The above peptides/sequences are highly suitable as peptides for SADCs which reduce neutralization of AdV vectors.

Example 15: Epitope mapping of monoclonal antibody 9C12 against AdV

Monoclonal antibody 9C12 (alias mAB TC31-9C12.C9-s) was generated by immunizing mice with the hexon protein (Uniprot ID: P04133 which corresponds to GenBank: BAG48782.1). This neutralizing antibody is directed against the hexon protein and the neutralizing activity of this antibody was demonstrated by Varghese (Varghese et al, 2004). In brief, diluted antibody was incubated with GFP-expressing replication-defective Ad vector and subsequently added to HeLa cells followed by fluorescence readout. In order to map a region from which paratope binding peptides could be derived, the sequence at amino acid positions 1 to 952 of GenBank: BAG48782.1 was used as a starting sequence for designing cyclic 7mer, lOmer and 13mer peptides that were then synthesized and circularized on a peptide microarray, and subsequently incubated with various concentrations of the antibody. The binding signal of mAb 9C12 to the peptides yielded several candidates that could be aligned and clustered against the protein. An epitopic cluster region of 20 amino acids was identified from which paratope binding peptides can be preferentially derived. Below are the aligments of the corresponding peptide hits from this screen. The number of the peptide names corresponds to the ranked binding signal obtained from the microarray (i.e. peptide 01 binds strongest, 02 second strongest, etc.). Cyclic peptides were selected out of up to 50 top binders in this experiment.

The above peptides/sequences are highly suitable as peptides for SADCs which reduce neutralization of AdV vectors.

Example 16: Epitope mapping of polyclonal antibody ab6982 against AdV

Polyclonal antibody ab6982 (Abeam) was generated by immunizing rabbits with purified AdV. It reacts with all capsid proteins of Ad5 including hexon, fiber and penton. It was shown that the antibody neutralizes Ad5 infection in a bioassay at 1000 adenovirus 5 particles / ml, a 50 % inactivation of the adenovirus can be achieved at a 1/25,000 dilution of the antibody. In order to identify epitopic regions that could contain peptides for ab6982 paratope binding, the antibody was mapped against the sequences of fiber (NCBI Reference Sequence: AP_000226.1) and hexon protein (GenBank: BAG48782.1). The fibersequence at amino acid positions 1 to 581 of (NCBI Reference Sequence: AP_000226.1), and the hexon-sequene (GenBank: BAG48782.1) at amino acid positions 1 to 952 were used as a starting sequence for designing 7mer, lOmer and 13mer cyclic peptides synthesized on a peptid array. The binding signal of this antibody to the array yielded several peptides that were aligned and clustered against the sequence of the protein. The peptide clusters were named clusterl-7 (fiber protein) and clusters8-16 (hexon protein) according to their ranked order of cyclic peptide hits (i.e. cluster contains the strongest binders, cluster! the second strongest etc.). Below are the alignments of the corresponding peptides that bind to polyclonal antibody ab6982. The number of the peptide names corresponds to the antibody binding signal ranking from the microarray experiment, the numbers of the clusters 1-7 and clusters 8-16 are ranked by the content of top binding peptides, respectively. 190 - QMLANYNIGYQGF- (SEQ ID NO: 311)

The above peptides/sequences are highly suitable as peptides for SADCs which reduce neutralization of AdV vectors. Importantly, binding of these peptides to the paratope of unwanted antibodies can be even further improved by mutating 1, 2 or 3 amino acids in order to generate mimotopes with improved antibody binding properties.

Example 17: Epitope mapping of mAb ADK8 against AAV

Monoclonal antibody ADK8 was generated by immunizing mice with AAV8 capsids. It is directed against the assembled AAV8 capsid (Sonntag et al, 2011). The neutralizing function of the antibody was previously demonstrated (Gurda et al, 2012). In brief, AAV8 was pre-incubated with ADK8 which lead to a decline in the number of virus particles present in the cytoplasm. Moreover, the binding of AAV8 to the nuclear membrane as well as the nuclear entry were abrogated following neutralization by ADK8. This suggests that ADK8 neutralization might interfere either with the cellular entry and / or the transport to the nucleus. ADK8 also cross-reacts with capsid proteins from other AAV serotypes such as AAV1, AAV3, AAV7 (Mietzsch et al, 2014) and was therefore chosen as an example from which general conclusions about the present invention can be drawn.

As for the other antibodies (see examples above), several clusters were identified, delineating regions from which preferred peptides can be deduced. Most preferably, the peptides aligned below according to their binding strengths can be used for selective antibody depletion and detection as hereinabove.

Example 18: Screen for anti-AAV antibodies in human sera

2452 linear peptides derived from the sequences of 16 different AAVs used in gene therapy and with a sequence length of 15 amino-acids each were synthesized.

Samples obtained from human donors were screened for antibodies against these AAV-derived peptides immobilized on microarrays. To this end, IgG was prepared from blood obtained from the human donors by protein G purification. Each IgG sample was incubated with the peptide microarrays and Ig binding signals were detected by fluorescence. All antibody binding signals to the peptides on the arrays were background subtracted and ranked for each sample and a deduplicated aggregate of the respective top 250 peptide hits for each donor with the corresponding protein sequence of origin (as obtained from UniProt or other sources) was compiled (designated as group TV). Further, the deduplicated aggregate of the respective top 50 peptide hits for each donor was compiled and designated as group ITT. Further, the deduplicated aggregate of the respective top 25 peptide hits for each donor was compiled and designated as group IT. Finally, the deduplicated aggregate of the respective top 10 peptide hits for each donor was compiled and designated as group I.

Detailed results are shown in Table 1 below. Altogether, group I contains 110 distinct peptide hits (assigned to the corresponding AAV vectors in Table 1), group IT contains 289 distinct peptide hits, group ITT contains 428 distinct peptide hits and group TV contains 1271 distinct peptide hits. Evidently, group I is a subset of group IT which in turn is a subset of group ITT which in turn is a subset of group TV. Groups I-IV correspond to the top 4.4%, 10.5%, 17.5% and 51.8%, respectively, of all peptides screened.

Thus, all listed peptides, preferably peptides belonging to group ITT, even more preferably belonging to group IT and most preferably belonging to group I (i.e. to the top 4.4%), provide sequences from which shorter peptide sequences can be derived for antibody depletion according to the present invention. Furthermore, also other peptide sequences (or fragments) from the proteins from which the peptides of Table 1 were derived (preferably from group ITT, more preferably however from group IT, most preferably from group I), are suited to be used for SADCs according to the present invention. In addition, these peptides can also be used as probes for the diagnostic detection of anti-AAV antibodies in biological samples such as human sera.

Table 1

This table lists the detailed results of a screen for linear peptides as a basis for the construction of anti-AAV antibody depleting SADCs according to the present invention. These peptides are also suitable typing neutralizing antibodies directed against AAV gene therapy vectors. If not stated otherwise, the peptides represent fragments from different AAV VP1 proteins. Source given is either UniProt ID, GenBank ID, PDB ID or AAV strain name. Q Q X 056137

Example 19: Screen for anti-AAV antibodies in human sera based on cyclic peptides

More than 1200 cyclic peptides derived from the sequences of human and rhesus monkey AAV sequences and artificial AAV sequences according to Table 2 and with a sequence length of 14 amino-acids each were synthesized.

Samples obtained from human donors were screened for antibodies against these AAV-derived peptides immobilized on microarrays. To this end, IgG was prepared from blood obtained from the human donors by protein G purification. Each IgG sample was incubated with the peptide microarrays and Ig binding signals were detected by fluorescence. All antibody binding signals to the peptides on the arrays were background subtracted and ranked for each sample and a deduplicated aggregate of the respective top 250 peptide hits for each donor with the corresponding protein sequence of origin (as obtained from UniProt or other sources) was compiled (designated as group II). Further, the deduplicated aggregate of the respective top 50 peptide hits for each donor was compiled and designated as group I . Detailed results are shown in Table 2 below. Altogether, group I contains 47 distinct peptide hits (assigned to the corresponding AAV vectors in Table 2) and group IT yielded 172 distinct peptide hits. Evidently, group I is a subset of group IT.

Thus, all listed peptides, preferably peptides belonging to group I, provide sequences from which shorter peptide sequences can be derived for antibody depletion according to the present invention. Furthermore, also other peptide sequences (or fragments) from the proteins from which the peptides of Table 2 were derived (preferably from group I), are suited to be used for SADCs according to the present invention. In addition, these peptides can also be used as probes for the diagnostic detection of anti-AAV antibodies in biological samples such as human sera.

Table 2

This table lists the detailed results of a screen for circularized peptides as a basis for the construction of anti- AAV antibody depleting SADCs according to the present invention. These peptides are also suitable for typing neutralizing antibodies directed against AAV gene therapy vectors. If not stated otherwise, the peptides represent fragments from different AAV VP1 proteins. Source given is either UniProt ID, GenBank ID, PDB ID or AAV strain name.

Example 20: Further screen for anti-AAV antibodies in human sera

By using a cumulative gliding average signal of all sera tested over 4 consecutively aligned peptide signals along the corresponding AAV sequences, 1948 linear peptides were derived from AAV vectors AAV1, AAV2, AAV5, AAV6, AAV8, AAV9 and AAVrh .10.

Detailed results are shown in Table 3 below. 63 top candidates with the strongest signals were assigned to group I corresponding to 3.2 % of all AAV peptides analyzed by gliding average signal along the AAV VP1 sequence. The peptides of group I as well as the 135 peptides with second strongest signals were assigned to group IT corresponding to 10.1 % of all AAV peptides analyzed. Additional 82 peptides (assigned to group ITT) were derived from the top 200 ranked peptide signals of the present screen not covered by group I and IT. In summary, groups I, II and III thus contain 280 linear peptides suitable (as basis for SADCs) to remove or to detect anti AAV antibodies, in particular antibodies directed against the AAV1, AAV2, AAV5, AAV6, AAV8, AAV9 and AAVrh.10 VP1 proteins.

Table 3

This table provides a separate compilation of suitable peptides covering stretches along the VP1 sequence of widely used AAV vectors including AAV1, AAV2, AAV5, AAV6, AAV8, AAV9 and AAVrh.10. Source given is either UniProt ID, GenBank ID, PDB ID or AAV strain name. The asterisk (*) indicates peptide sequences for which a SEQ ID NO has already been assigned in Table 1 above.

Example 21: Further screen for anti-vector antibodies in human sera

Out of the 3285 cyclic peptides derived from Ad5 Hexon, fiber and penton proteins P04133, P11818 and P12538, respectively, and AAV VP1 sequences P03135, Q6JC40, Q8JQF8, Q9WBP8, Q9YIJ1, 056137, AAO88201.1, 041855, 056139 and Q8JQG0, the peptides with the top 5% maximal IgG signal strength over the microarray screens were obtained, yielding a total of 164 peptides with top signals from the vector protein sequences screened. The details are shown in Table 4 below.

Table 4

This table provides another compilation of viral peptide sequences suitable as a basis for the present invention. Source given is either UniProt ID or GenBank ID. The asterisk (*) indicates peptide sequences for which a SEQ ID NO has already been assigned in Table 2 above. Non-patent references

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