Title:
AQUEOUS IMMUNOLOGIC ADJUVANT COMPOSITIONS OF MONOPHOSPHORYL LIPID A
Document Type and Number:
WIPO Patent Application WO/2000/078353
Kind Code:
A2
Abstract:
An aqueous adjuvant composition comprising an attenuated lipid A derivative and a non-immunostimulatory surfactant or surfactants enhances the immunological response in a warm blooded animal to a protein antigen. Attenuated lipid A derivatives useful according to the subject invention include monophosphoryl lipid A and 3-O-deacylated monophosphoryl lipid A. A surfactant or mixtures of surfactants are dissolved in a solvent. 1,2 Dipalmitoyl-sn-glycero-3-phosphocholine is a preferred surfactant. The dissolved surfactant is added to an attenuated lipid A derivative to obtain a mixture. The molar ratio of attenuated lipid A derivative to surfactant in the mixture is about 4:1. The solvent is evaporated and water is added to the resulting film. The suspension is sonicated in a 60 °C water bath until it becomes clear. Animals administered the adjuvant formulation exhibited increased antibody responses to a given antigen as well as displayed enhanced lymphocyte proliferative and cytotoxic T-lymphocyte responses. Intranasal administration of the aqueous adjuvant composition and an antigen stimulates the production of serum and mucosal secreted IgA.
Inventors:
CRANE R THOMAS
Application Number:
PCT/US2000/016384
Publication Date:
December 28, 2000
Filing Date:
June 14, 2000
Export Citation:
Assignee:
CORIXA CORP (US)
International Classes:
A61K9/08; A61K9/00; A61K35/74; A61K39/04; A61K39/08; A61K39/29; A61K39/39; A61K47/10; A61K47/16; A61K47/18; A61K47/36; A61P37/04; C07H13/06; A61K9/127; A61K39/00; (IPC1-7): A61K47/00
Domestic Patent References:
| WO1998043670A2 | 1998-10-08 | |||
| WO1994021292A1 | 1994-09-29 | |||
| WO1999056776A2 | 1999-11-11 |
Foreign References:
| GB2220211A | 1990-01-04 |
Other References:
S. SASAKI ET AL.: "Monophosphoryl lipid A enhances both humoral and cell-mediated immune responses to DNA vaccination against human immunodeficiency virus type 1." INFECTION AND IMMUNITY, vol. 65, no. 9, September 1997 (1997-09), pages 3520-3528, XP002075736 Washington, DC, USA
C. BOECKLER ET AL.: "Immunogenicity of new heterobifunctional cross-linking reagents used in the conjugation of synthetic peptides to liposomes." JOURNAL OF IMMUNOLOGICAL METHODS, vol. 191, no. 1, 10 May 1996 (1996-05-10), pages 1-10, XP002075734 Amsterdam, The Netherlands
A. VERHEUL ET AL.: "Beneficial effects of additional adjuvants on the immune response to haptenated liposomes." JOURNAL OF LIPOSOME RESEARCH, vol. 6, no. 2, 1996, pages 397-414, XP002075735 New York, NY, USA
C. BOECKLER ET AL.: "Immunogenicity of new heterobifunctional cross-linking reagents used in the conjugation of synthetic peptides to liposomes." JOURNAL OF IMMUNOLOGICAL METHODS, vol. 191, no. 1, 10 May 1996 (1996-05-10), pages 1-10, XP002075734 Amsterdam, The Netherlands
A. VERHEUL ET AL.: "Beneficial effects of additional adjuvants on the immune response to haptenated liposomes." JOURNAL OF LIPOSOME RESEARCH, vol. 6, no. 2, 1996, pages 397-414, XP002075735 New York, NY, USA
Attorney, Agent or Firm:
Kyle, Jean (Lloyd & Saliwanchik P.C. P.O. Box 2274 Hamilton, MT, US)
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Claims:
Claims
| 1. | An aqueous adjuvant composition comprising an attenuated lipid A derivative and one or more nonimmunostimulatory surfactants. |
| 2. | The aqueous adjuvant composition of claim 1, wherein said attenuated lipid A derivative is selected from the group consisting of monophosphoryl lipid A or 3Odeacylated monophosphoryl lipid A. |
| 3. | The aqueous adjuvant composition of claim 1, wherein said attenuated lipid A derivative is monophosphoryl lipid A. |
| 4. | The aqueous adjuvant composition of claim 1, wherein said attenuated lipid A derivative is 30deacylated monophosphoryl lipid A. |
| 5. | The aqueous adjuvant composition of claim 1, wherein said non immunostimulatory surfactant is selected from the group consisting of glycodeoxycholate, deoxycholate, sphingomyelin, sphingosine, phosphatidylcholine, 1,2Dimyristoylsnglycero3phosphoethanolamine, La Phosphatidylethanolamine, and 1,2Dipalmitoylsnglycero3phosphocholine, or a mixture thereof. |
| 6. | The aqueous adjuvant composition of claim 1, wherein said non immunostimulatory surfactant is 1,2Dipalmitoylsnglycero3phosphocholine. |
| 7. | The aqueous adjuvant composition of claim 1, wherein the molar ratio of attenuated lipid A derivative to nonimmunostimulatory surfactant is from about 10: 1 to about 10: 5. |
| 8. | The aqueous adjuvant composition of claim 1, wherein the molar ratio of attenuated lipid A derivative to nonimmunostimulatory surfactant is about 4: 1. |
| 9. | The aqueous adjuvant composition of claim 1, further comprising glycerol. |
| 10. | The aqueous adjuvant composition of claim 9, wherein glycerol is from about 2 percent volume to volume to about 40 percent volume to volume of said composition. |
| 11. | The aqueous adjuvant composition of claim 9, wherein glycerol is from about 2 percent volume to volume to about 10 percent volume to volume of said composition. |
| 12. | A method of making an aqueous adjuvant composition comprising the steps of : a) dissolving one or more nonimmunostimulatory surfactants in a solvent; b) mixing the dissolved surfactants with an attenuated lipid A derivative to obtain a mixture of the attenuated lipid A derivative and the surfactants; c) evaporating the solvent from the mixture of surfactants and attenuated lipid A derivative; d) adding water to the evaporated mixture to obtain a suspension; and e) heating and sonicating the suspension of step d until clear. |
| 13. | The method of claim 12, wherein said attenuated lipid A derivative is selected from the group consisting of monophosphoryl lipid A and 3Odeacylated monophosphoryl lipid A. |
| 14. | The method of claim 12, wherein said attenuated lipid A derivative is monophosphoryl lipid A. |
| 15. | The method of claim 12, wherein said attenuated lipid A derivative is 3 Odeacylated monophosphoryl lipid A. |
| 16. | The method of claim 12, wherein said nonimmunostimulatory surfactant is selected from a group consisting of glycodeoxycholate, deoxycholate, sphingomyelin, sphingosine, phosphatidylcholine, 1,2Dimyristoylsnglycero3 phosphoethanolamine, LaPhosphatidylethanolamine, and 1,2Dipalmitoylsn glycero3phosphocholine, or a mixture thereof. |
| 17. | The method of claim 12, wherein said nonimmunostimulatory surfactant is 1,2Dipalmitoylsnglycero3phosphocholine. |
| 18. | The method of claim 12, wherein the molar ratio of attenuated lipid A derivative to nonimmunostimulatory surfactant is from about 10: 1 to about 10: 5. |
| 19. | The method of claim 12, wherein the molar ratio of attenuated lipid A derivative to nonimmunostimulatory surfactant is about 4: 1. |
| 20. | The method of claim 12, wherein said solvent is selected from the group consisting of chloroform, alcohols, dimethyl sulfoxide and dimethylformamide or mixtures thereof. |
| 21. | The method of claim 12, wherein said solvent is ethanol. |
| 22. | The method of claim 12, wherein said suspension is heated to from about 60°C to about 80 °C. |
| 23. | The method of claim 12, wherein said suspension is heated to about 60 °C. |
| 24. | The method of claim 12, wherein said suspension is sonicated for about 5 to 60 minutes. |
| 25. | The method of claim 12, wherein said suspension is sonicated for about 10 minutes. |
| 26. | The method of claim 12, further comprising the steps of : (f) adding from about 2 to about 40 percent volume to volume glycerol. |
| 27. | The method of claim 26, wherein said glycerol is added at from about 2 to about 10 percent volume to volume. |
| 28. | The method of claim 12, further comprising the steps of : (f) adding from about 2 to about 40 percent volume to volume glycerol; and (g) lyophilizing said composition. |
| 29. | A method of enhancing the immune response of a warmblooded animal to a protein antigen which is capable of eliciting an immune response in the animal, the method comprising the steps of administering to the animal one or more protein antigens and an effective amount of an aqueous adjuvant composition which comprises an attenuated lipid A derivative and one or more nonimmunostimulatory surfactants. |
| 30. | 3 0. |
| 31. | The method of claim 29, wherein said attenuated lipid A derivative is selected from the group consisting of monophosphoryl lipid A and 3Odeacylated monophosphoryl lipid A. |
| 32. | The method of claim 29, wherein said aqueous adjuvant composition is administered intranasally. |
| 33. | The method of claim 29, wherein said composition further comprises from about 2 percent to about 40 percent volume to volume glycerol. |
| 34. | A method of stimulating a serum and mucosal secretory IgA response of a warmblooded animal to a protein antigen which is capable of eliciting an immune response in the animal, the method comprising the steps of administering to the animal one or more protein antigens and an effective amount of an aqueous adjuvant composition which comprises an attenuated lipid A derivative and one or more nonimmunostimulatory surfactants. |
| 35. | The method of claim 33, wherein said attenuated lipid A derivative is selected from the group consisting of monophosphoryl lipid A and 3Odeacylated monophosphoryl lipid A. |
| 36. | The method of claim 33, wherein said aqueous adjuvant composition is administered intranasally. |
| 37. | The method of claim 33, wherein said composition further comprises from about 2 percent to about 40 percent volume to volume glycerol. |
Description:
INTERNATIONALSEARCHREPORT Inter nal Application No PCT/US00/16384 C.(Continuation)DOCUMENTSCONSIDEREDTOBERELEVANT CategoryCitationofdocument,withindication.whereappropriate,o
ttherelevantpassagesRelevanttoclaimNo. XS.SASAKIET AL.: "Monophosphoryllipid A1-3,29, enhancesbothhumoralandcell-mediated30,33,34 immuneresponsestoDNAvaccination againsthumanimmunodeficiencyvirustype 1." INFECTIONANDIMMUNITY, vol.65,no.9,September1997(1997-09), pages3520-3528,XP002075736 Washington,DC,USA abstract page3521,left-handcolumn,line25- line26 AC.BOECKLER ET AL. :"Immunogenicity of1-36 newheterobifunctionalcross-linking reagentsusedintheconjugationof syntheticpeptidestoliposomes." JOURNALOFIMMUNOLOGICALMETHODS, vol.191,no.1,10May1996(1996-05-10), pages1-10,XP002075734 Amsterdam,TheNetherlands abstract figure1 AA.VERHEULETAL.:"Beneficialeffectsof1-36 additionaladjuvantsontheimmune responsetohaptenatedliposomes." JOURNALOFLIPOSOMERESEARCH, vol.6,no.2,1996,pages397-414, XP002075735 NewYork,NY,USA page399 P,XWO9956776A(RIBIIMMUNOCHEMRESEARCH)1-36 11November1999(1999-11-11) examples claims 1 INTERNATIONALSEARCHREPORT Internal Application No Informationonpatentfamilymembers PCT/US00/16384 PatentdocumentPublication PatentfamilyPublication citedinsearchreportdate member(s)date WO9843670A08-10-1998AU 6947398 A 22-10-1998 BR 9811262 A 17-10-2000 CN 1259052 T 05-07-2000 EP 0971739 A 19-01-2000 HU 0001403 A 28-09-2000 NO 994760 A 26-11-1999 PL 336698 A 03-07-2000 WO9421292A29-09-1994AP 515 A 09-08-1996 AT 157882 T 15-09-1997 AU 685443 B 22-01-1998 AU 6426494 A 11-10-1994 AU 705739 B 03-06-1999 AU 7541696 A 13-02-1997 BR 9405957 A 12-12-1995 CA 2157376 A 29-09-1994 CN 1119829 A 03-04-1996 CZ 9502467 A 13-03-1996 DE 69405551 D 16-10-1997 DE 69405551 T 26-03-1998 DK 689454 T 08-12-1997 EP 0689454 A 03-01-1996 EP 0812593 A 17-12-1997 ES 2109685 T 16-01-1998 FI 954514 A 22-09-1995 GR 3025483 T 27-02-1998 HU 72916 A 28-06-1996 IL 109056 A 15-06-1998 JP 8508722 T 17-09-1996 NO 953759 A 22-09-1995 NZ 263538 A 28-10-1996 PL 310598 A 27-12-1995 SG 48309 A 17-04-1998 SK 117395 A 06-11-1996 US 5776468 A 07-07-1998 ZA 9401957 A 31-01-1995 GB2220211A04-01-1990US 4912094 A 27-03-1990 CA 1317589 A 11-05-1993 DE 3921416 A 04-01-1990 WO9956776A11-11-1999AU 3973799 A 23-11-1999
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