Claims
- 1. A method of enhancing an immune response in an animal, comprising administering to an animal in need of such enhancing a polysaccharide conjugate in an amount effective to enhance the immune response of said animal, wherein said polysaccharide conjugate consists essentially of:
(i) a polysaccharide which binds to the surface of Antigen Presenting Cells (APCs) wherein said polysaccharide comprises a minimum of seven saccharides; and (ii) one or more molecules having a stable carbonyl group; wherein polysaccharide (i) is attached to molecules (ii) through (iii) a direct covalent bond or covalently via a bifunctional linker in a manner that keeps the stable carbonyl group intact.
- 2. The method of claim 1, wherein said one or more molecules having a stable carbonyl group (ii) are selected from the group consisting of aromatic aldehydes, aromatic ketones, cycloalkyl aldehydes, cycloalkyl ketones, cycloalkenyl aldehydes, cycloalkenyl ketones, heterocyclic aldehydes, heterocyclic ketones, heteroaromatic ketones, heteroaromatic aldehydes, alkyl aldehyde, alkyl ketones, alkenyl aldehydes and alkenyl ketones.
- 3. The method of claim 1, wherein said molecules having a stable carbonyl group are bound to said polysaccharide via a direct covalent bond.
- 4. The method of claim 1, wherein said molecules having a stable carbonyl group are bound to said polysaccharide via a residue of a bifunctional linker molecule.
- 5. The method of claim 1, wherein said polysaccharide is selected from the group consisting of β-glucans, mannans, pectic polysaccharides and 2-acetamido glucan polysaccharides.
- 6. The method of claim 1, wherein said molecules having a stable carbonyl group are selected from the group consisting of mono- and di-substituted C6-10 arylaldehydes, C6-10 aryl(C1-4)alkylaldehydes, and mixtures thereof.
- 7. The method of claim 1, wherein said molecules having a stable carbonyl group are phenyl or naphthyl substituted by a formyl or formyl(C1-4)alkyl substituent, and optionally including one or two additional substituents independently selected from the group consisting of halo, hydroxy, C1-4 alkyl, C1-4 alkoxy, trifluoromethyl, and benzyloxy.
- 8. The method of claim 1, wherein said molecules having a stable carbonyl group are benzaldehyde and naphthaldehyde, substituted by one or two of hydroxy and halo.
- 9. The method of claim 1, wherein said molecules having a stable carbonyl group are 2,3-, 2,4-2,5-, and 3,4-dihydroxybenzaldehyde, 5-chloro-2-hydroxybenzaldehyde, vanillin, ethyl vanillin, naringenin, 3- and 4-hydroxybenzaldehyde, or 4-hydroxyphenylacetaldehyde.
- 10. The method of claim 1, wherein said molecules having a stable carbonyl group are selected from the group consisting of hydroxy substituted C1-4 alkyl (C6-10)aryl ketones, and hydroxy substituted aryl ketones.
- 11. The method of claim 1, wherein said molecules having a stable carbonyl group are selected from the group consisting of 2-hydroxyacetophenone, 3-hydroxyacetophenone, 4-hydroxyacetophenone, and 6-hydroxy-1,2-naphthoquinone.
- 12. The method of claim 1, wherein said molecules having a stable carbonyl group are selected from the group consisting of heteroaryl aldehydes and heteroaryl ketones.
- 13. The method of claim 1, wherein said molecules having a stable carbonyl group are thiophene, furan, benzothiophene, benzofuran, pyridine, quinoline, pyridazine, pyrimidine, pyrazole, imidazole, 1,2,3-riazole, 1,2,4-triazole, isoxazole, or oxazole, each having a keto, formyl or formyl(C1-4) substituent, and preferably including an additional halo or hydroxy substituent, if these can be accommodated by available ring carbon atoms.
- 14. The method of claim 1, wherein said molecules having a stable carbonyl group is one of pyridoxal, 2-thiophenecarboxaldehyde, and 3-thiophenecarboxaldehyde.
- 15. The method of claim 4, wherein said residue of a bifunctional linker molecule is selected from the group consisting of:
H2N—CH2)r—NH2, where r is from 2 to 12; HO—CH2)r—NH2, where r is from 2 to 12; HS—(CH2)r—NH2, where r is from 2 to 12; amino acids that are optionally carboxy-protected; and H—(O—CH2—CH2)n—H, where n is 1-4.
- 16. The method of claim 4, wherein said bifunctional linker molecule is selected from the group consisting of: ethylenediamine, 1,4-butanediamine, spermidine, 2,4-diaminobutyric acid, lysine, β-alanine, γ-aminobutyric acid, dialanine, trialanine, 3,3′-diaminodipropylamine, diaminopropionic acid, N-(2-aminoethyl)-1,3-propanediamine, and 2-(4-aminophenyl)ethylamine.
- 17. The method of claim 4, wherein said bifunctional linker molecule is selected from the group consisting of:
—NH—CH2)r—NH—, where r is from 2-5, —O—CH2)r—NH—, where r is from 2-5, —NH—CH2—C(O)—, —O—CH2—CH2—O—CH2—CH2—, —NH—NH—C(O)—CH2—, —NH—C(CH3)2—C(O)—, —S—(CH2)r—C(O)—, where r is from 1-5, —S—(CH2)r—NH—, where r is from 2-5, —S—(CH2)r—O—, where r is from 1-5, —S—CH2)—CH(NH2)—C(O)—, —S—(CH2)—CH(COOH)—NH—, —O—CH2—CH(OH)—CH2—S—CH(CO2H)—NH—, —O—CH2—CH(OH)—CH2—S—CH(NH2)—C(O)—, —O—CH2—CH(OH)—CH2—S—CH2—CH2—NH—, —S—CH2—C(O)—NH—CH2—CH2—NH—, and —NH—O—C(O)—CH2—CH2—O—P(O2H)—.
- 18. The method of claim 1, wherein said polysaccharide is selected from the group consisting of: β-glucans, mannans, pectic polysaccharides, chitin and its derivatives, murein, bacterial fructans, xanthans, bacterial heteropolysaccharides, fungal pullulan, and esters, sulfonates, sulfates, phosphates; ethers, and cross-linked derivatives thereof.
- 19. The method of claim 1, wherein said polysaccharide is a β-glucan having a backbone chain of (1→3)-linked β-D-glucopyranosyl units and which has β-D-glucopyranosyl units attached by (1→6) linkages, and a molecular weight of between about 5,000 to about 500,000, and wherein said β-glucan is optionally modified by the addition of one or more anionic, cationic or non-ionic groups.
- 20. The method of claim 1, wherein said polysaccharide is a β-mannans comprising (1→4) polymannose having a terminus reducing mannosyl residue, or the acetylation product thereof.
- 21. The method of claim 1, wherein said polysaccharide is a pectic polysaccharide selected from the group consisting of homogalacturonans, rhamnogalacturonans, arabans, galactans, and arabinogalactans, and wherein said pectic polysaccharide possesses immunopotentiating activity.
- 22. A method of potentiating an immune response to an antigen in an animal, comprising administering a polysaccharide conjugate in an effective amount to potentiate the immune response of said animal to said antigen, wherein said polysaccharide conjugate consists essentially of:
(i) a polysaccharide which binds to the surface of Antigen Presenting Cells (APCs) wherein said polysaccharide comprises a minimum of seven saccharides; and (ii) one or more molecules having a stable carbonyl group; wherein polysaccharide (i) is attached to molecules (ii) through (iii) a direct covalent bond or covalently via a bifunctional linker in a manner that keeps the stable carbonyl group intact.
- 23. The method of claim 22, wherein said one or more molecules having a stable carbonyl group (ii) are selected from the group consisting of aromatic aldehydes, aromatic ketones, cycloalkyl aldehydes, cycloalkyl ketones, cycloalkenyl aldehydes, cycloalkenyl ketones, heterocyclic aldehydes, heterocyclic ketones, heteroaromatic ketones, heteroaromatic aldehydes, alkyl aldehyde, alkyl ketones, alkenyl aldehydes and alkenyl ketones.
- 24. The method of claim 22, wherein said molecules having a stable carbonyl group are bound to said polysaccharide via a direct covalent bond.
- 25. The method of claim 22, wherein said molecules having a stable carbonyl group are bound to said polysaccharide via a residue of a bifunctional linker molecule.
- 26. The method of claim 22, wherein said polysaccharide is selected from the group consisting of β-glucans, mannans, pectic polysaccharides and 2-acetamido glucan polysaccharides.
- 27. The method of claim 22, wherein said molecules having a stable carbonyl group are selected from the group consisting of mono- and di-substituted C6-10 arylaldehydes, C6-10 aryl(C1-4)alkylaldehydes, and mixtures thereof.
- 28. The method of claim 22, wherein said molecules having a stable carbonyl group are phenyl or naphthyl substituted by a formyl or formyl(C1-4)alkyl substituent, and optionally including one or two additional substituents independently selected from the group consisting of halo, hydroxy, C1-4 alkyl, C1-4 alkoxy, trifluoromethyl, and benzyloxy.
- 29. The method of claim 22, wherein said molecules having a stable carbonyl group are benzaldehyde and naphthaldehyde, substituted by one or two of hydroxy and halo.
- 30. The method of claim 22, wherein said molecules having a stable carbonyl group are 2,3-, 2,4-2,5-, and 3,4-dihydroxybenzaldehyde, 5-chloro-2-hydroxybenzaldehyde, vanillin, ethyl vanillin, naringenin, 3- and 4-hydroxybenzaldehyde, or 4-hydroxyphenylacetaldehyde.
- 31. The method of claim 22, wherein said molecules having a stable carbonyl group are selected from the group consisting of hydroxy substituted C1-4alkyl (C6-10)aryl ketones, and hydroxy substituted aryl ketones.
- 32. The method of claim 22, wherein said molecules having a stable carbonyl group are selected from the group consisting of 2-hydroxyacetophenone, 3-hydroxyacetophenone, 4-hydroxyacetophenone, and 6-hydroxy-1,2-naphthoquinone.
- 33. The method of claim 22, wherein said molecules having a stable carbonyl group are selected from the group consisting of heteroaryl aldehydes and heteroaryl ketones.
- 34. The method of claim 22, wherein said molecules having a stable carbonyl group are thiophene, furan, benzothiophene, benzofuran, pyridine, quinoline, pyridazine, pyrimidine, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, isoxazole, or oxazole, each having a keto, formyl or formyl(C1-4) substituent, and preferably including an additional halo or hydroxy substituent, if these can be accommodated by available ring carbon atoms.
- 35. The method of claim 22, wherein said molecules having a stable carbonyl group is one of pyridoxal, 2-thiophenecarboxaldehyde, and 3-thiophenecarboxaldehyde.
- 36. The method of claim 25, wherein said residue of a bifunctional linker molecule is selected from the group consisting of:
H2N—(CH2)r—NH2, where r is from 2 to 12; HO—(CH2)r—NH2, where r is from 2 to 12; HS—(CH2)r—NH2, where r is from 2 to 12; amino acids that are optionally carboxy-protected; and H—(O—CH2—CH2)n—OH, where n is 1-4.
- 37. The method of claim 25, wherein said bifunctional linker molecule is selected from the group consisting of: ethylenediamine, 1,4-butanediamine, spermidine, 2,4-diaminobutyric acid, lysine, β-alanine, γ-aminobutyric acid, dialanine, trialanine, 3,3′-diaminodipropylamine, diaminopropionic acid, N-(2-aminoethyl)-1,3-propanediamine, and 2-(4-aminophenyl)ethylamine.
- 38. The method of claim 25, wherein said bifunctional linker molecule is selected from the group consisting of:
—NH—(CH2)r—NH—, where r is from 2-5, —O—(CH2)r=NH—, where r is from 2-5, —NH—CH2—C(O)—, —O—CH2—CH2—O—CH2—CH2—O—, —NH—NH—C(O)—CH2—, —NH—C(CH3)2—C(O)—, —S—(CH2)r—C(O)—, where r is from 1-5, —S—(CH2)r—NH—, where r is from 2-5, —S—(CH2)r—O—, where r is from 1-5, —S—(CH2)—CH(NH2)—C(O)—, —S—(CH2)—CH(COOH)—NH—, —O—CH2—CH(OH)—CH2—S—CH(CO2H)—NH—, —OCH2—CH(OH)—CH2—S—CH(NH2)—C(O)—, —O—CH2—CH(OH)—CH2—S—CH2—CH2—NH—, —S—CH2—C(O)—NH—CH2—CH2—NH—, and —NH—O—C(O)—CH2—CH2—O—P(O2H)—.
- 39. The method of claim 22, wherein said polysaccharide is selected from the group consisting of: β-glucans, mannans, pectic polysaccharides, chitin and its derivatives, murein, bacterial fructans, xanthans, bacterial heteropolysaccharides, fungal pullulan, and esters, sulfonates, sulfates, phosphates; ethers, and cross-linked derivatives thereof.
- 40. The method of claim 22, wherein said polysaccharide is a β-glucan having a backbone chain of (1→3)-linked β-D-glucopyranosyl units and which has β-D-glucopyranosyl units attached by (1→6) linkages, and a molecular weight of between about 5,000 to about 500,000, and wherein said β-glucan is optionally modified by the addition of one or more anionic, cationic or non-ionic groups.
- 41. The method of claim 22, wherein said polysaccharide is a β-mannans comprising (1→4) polymannose having a terminus reducing mannosyl residue, or the acetylation product thereof.
- 42. The method of claim 22, wherein said polysaccharide is a pectic polysaccharide selected from the group consisting of homogalacturonans, rhamnogalacturonans, arabans, galactans, and arabinogalactans, and wherein said pectic polysaccharide possesses immunopotentiating activity.
- 43. A method of vaccinating an animal, comprising administering a polysaccharide conjugate to said animal, wherein said polysaccharide conjugate consists essentially of:
(i) a polysaccharide capable of binding to the cell surface of Antigen Presenting Cells (APCs) wherein said polysaccharide comprises a minimum of seven saccharides; and (ii) one or more molecules having a stable carbonyl group; wherein polysaccharide (i) is attached to molecules (ii) through (iii) a direct covalent bond or covalently via a bifunctional linker in a manner that keeps the stable carbonyl group intact.
- 44. A method of treating a disease in an animal comprising administering an effective amount of a polysaccharide conjugate, wherein said polysaccharide conjugate consists essentially of:
(i) a polysaccharide which binds to the surface of Antigen Presenting Cells (APCs) wherein said polysaccharide comprises a minimum of seven saccharides; and (ii) one or more molecules having a stable carbonyl group; wherein polysaccharide (i) is attached to molecules (ii) through (iii) a direct covalent bond or covalently via a bifunctional linker in a manner that keeps the stable carbonyl group intact.
- 45. The method of claim 44 further comprising the co-administration of at least one therapeutic agent or adjuvant.
- 46. The method of claim 44 or 45 wherein said disease is a cancer or a bacterial or viral infection or is the result of cancer or a bacterial or viral infection.
- 47. The method of claim 46 wherein said viral infection is the result of a virus selected from the group consisting of: herpes, Epstein Barr, rubella, papillovirus, and human immunodeficiency virus.
- 48. The method of claim 46 wherein said disease is hepatitis.
- 49. The method of claim 46 wherein said cancer is selected from the group consisting of: non-Hodgkins lymphoma, melanoma, breast, colon, head and neck, gastric, renal, laryngeal and rectal cancers, cancers that express antigens, cancers that contain tumor specific cytotoxic T-cells which are anergic, and cancers that have been surgically resected where there is a risk of recurrence.
- 50. The method of claim 46 wherein said disease is a Pneumocystis carinii infection.
- 51. The method of claim 44 or 45 wherein said disease is selected from the group consisting of: DiGeorge Syndrome, fungal infections, mycoplasma infections, tuberculosis, leprosy and systemic lupus erythemotosus.
- 52. The method of claim 45 wherein said adjuvant is an antigen.
- 53. The method of claim 51 wherein said antigen is derived from a virus, bacteria or protozoan.
- 54. The method of claim 52 wherein said antigen is derived from one of the following: influenza, feline leukemia, feline immunodeficiency virus, HIV-1, HIV-2, rabies, measles, hepatitis B, hoof and mouth disease, anthrax, diptheria, Lyme disease, tuberculosis, Babeosis bovis or Plasmodium.
- 55. The method of claim 45 wherein said therapeutic agent is an antiviral or anticancer agent.
- 56. The method of claim 55 wherein said antiviral agent is an agent for the treatment of viruses selected from the group consisting of: herpes, influenza, parainfluenza, adenoviruses, coxsakie, picorna, rotaviruses, hepatitis A, mumps, rubella, measles, pox, respiratory synctial, papilloma, enteroviruses, arenaviruses, rhinoviruses, polio, Newcastle disease, rabies and arboviruses.
- 57. The method of claim 55 wherein said antiviral agent is selected from the the group consisting of: 3′-azido-3′-deoxythymidine, 2′,3′-dideoxycytidine, 2′,3′-dideoxyadenosine, 2′,3′-dideoxyinosine, carbovir, 2′,3′-didehydrothymidine, N-tert-butyl-decahydro-2-[-2(R)-hydroxy-4-phenyl-3(S)-[[N-2-quinolylcarbonyl)-L-asparginyl]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide, cis-1-(2-hydroxymethyl)-1,3-oxathiolan-5-yl)-cytosine or cis-1-(2-(hydroxymethyl) -1 ,3-oxathiolan-5-yl)-5-fluoro-cytosine, 3′-deoxy-3′-fluorothymidine, 2′,3′-dideoxy-5-ethynyl-3′-fluorouridine, 5-chloro-2′,3′-dideoxy-3′-fluorouridine, Ribavirin, 9-[4-hydroxy-2-(hydroxymethyl)but-1-yl]guanine, 7-chloro-5-(2-pyrryl)-3H-1,4-benzodiazepine-2(H)-one, 7-chloro-1,3-dihydro-5-(1H-pyrrol-2-yl) -3H-1,4-benzodiazepin-2-amine, α-interferon, probenecid, dipyridamole; pentoxifylline, N-acetylcysteine, precession, α-trichosanthin, phosphonoformic acid, interleukin II, erythropoetin, and 1-(β-D-arabinofuranosyl)-5-propynyluracil.
- 58. The method of claim 45 wherein said adjuvant is selected from the group consisting of: oil adjuvants, saponins, modified saponins, liposomes, mineral salts, polynucleotides, certain natural substances isolated from Mycobacterium tuberculosis, Corynebacterium parvum, Bordetella pertussis or members of the genus Brucella, bovine serum, albumin, diptheria toroid, tetanus toroid, edestin, keyhole-limpet hemocyanin, Pseudomonal Toxin A, choleragenoid, cholera toxin, pertussis toxin, viral proteins, eukaryotic proteins, polysaccharide, RNA, polyvinylamine, polymethacrylic acid, polyvinylpyrrolidone, polycondensates, glycolipids, lipids and carbohydrates.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of earlier filed U.S. provisional patent application no. 60/060,786, filed Oct. 3, 1997, and is a divisional of U.S. patent application 09/165,310, filed Oct. 2, 1998, the contents of which are fully incorporated by reference herein.
Provisional Applications (1)
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Number |
Date |
Country |
|
60060786 |
Oct 1997 |
US |
Divisions (1)
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Number |
Date |
Country |
Parent |
09165310 |
Oct 1998 |
US |
Child |
10114465 |
Apr 2002 |
US |