Claims
- 1. A pharmaceutical composition comprising effective amounts of pharmacologically active agents, wherein said pharmacologically active agents comprise:
(a) an anti-human Fas antibody having an apoptosis inducing activity; and (b) a compound having a folate antagonistic activity or a dihydrofolate reductase inhibiting activity, the relative amounts of said active ingredients (a) and (b) being such that they exhibit a synergistic apoptosis inducing activity.
- 2. The pharmaceutical composition according to claim 1, wherein said anti-human Fas antibody having apoptosis inducing activity is a monoclonal antibody CH11, HFE7A or a humanized antibody thereof.
- 3. The pharmaceutical composition according to claim 1, wherein said anti-human Fas antibody having apoptosis inducing activity is a monoclonal antibody CH11 or a humanized antibody thereof.
- 4. The pharmaceutical composition according to claim 1, wherein said anti-human Fas antibody having apoptosis inducing activity is an anti-human Fas monoclonal antibody HFE7A produced by a mouse-mouse hybridoma HFE7A (FERM BP-5828) or a humanized antibody thereof.
- 5. The pharmaceutical composition according to claim 1, wherein said compound having a folate antagonist activity or a dihydrofolate reductase inhibiting activity is selected from the group consisting of methotrexate, edatrexate, epiroprim, iometrexol, pyritrexim, trimetrexate, brodimoprim, MX-68, N-[4-[3-(2,4-diamino-6,7-dihydro-5H-cyclopenta[d]-pyrimidin-5-yl)propyl]benzoyl]-L-glutamic acid, N-[[5-[2-(2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido[2,3-d]pyrimidin-6-yl)ethyl]-2-thienyl]carbonyl]-L-glutamic acid, (R)-N-[[5-[2-(2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido[2,3-d]pyrimidin-6-yl)ethyl]-2carbonyl]-L-glutamic acid, N-((2,4-diamino-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl)ethyl)-2-thienylcarbonyl-L-glutamic acid, (S)-2-[[[4-carboxy-4-[[4-[[(2,4-diamino-6-pteridinyl)methyl]amino]benzoyl]amino]butyl]amino]carbonyl]benzoic acid, N-[4-[3-(2,4-diamino-1H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoyl]-L-glutamic acid, 2,4-diamino-6-(N-(4-(phenylsulfonyl)benzyl)methylamino)quinazoline, 2,4-diamino-5-[4-[3-(4-aminophenyl-4-sulfonylphenylamino)propoxy]-3,5-dimethoxybenzyl]pyrimidine, N-[4-[4-(2,4-diamino-5-pyrimidinyl)butyl]benzoyl]-L-glutamic acid, N-[4-[3-(2,4-diamino-5-pyrimidinyl)propyl]benzoyl]-L-glutamic acid, N-[4-[2-(2,4-diamino-6-pteridinyl)ethyl]-benzoyl]-4-methylene-DL-glutamic acid and N-(l-methylethyl)-N-[3-(2,4,5-trichlorophenoxy)propoxy]imidodicarbonimidic diamide hydrochloride (PS15).
- 6. The pharmaceutical composition according to claim 2, wherein said compound having a folate antagonist activity or a dihydrofolate reductase inhibiting activity is selected from the group consisting of methotrexate, edatrexate, epiroprim, iometrexol, pyritrexim, trimetrexate, brodimoprim, MX-68, N-[4-[3-(2,4-diamino-6,7-dihydro-5H-cyclopenta[d]-pyrimidin-5-yl)propyl]benzoyl]-L-glutamic acid, N-[[5-[2-(2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido[2,3-d]pyrimidin-6-yl)ethyl]-2-thienyl]carbonyl]-L-glutamic acid, (R)-N-[[5-[2-(2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido[2,3-d]pyrimidin-6-yl)ethyl]-2-thienyl]-carbonyl]-L-glutamic acid, N-((2,4-diamino-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl)ethyl)-2-thienylcarbonyl-L-glutamic acid, 2-[[[4-carboxy-4-[[4-[[(2,4-diamino-6-pteridinyl)methyl]amino]benzoyl]amino]butyl]amino]carbonyl]benzoic acid, N-[4-[3-(2,4-diamino-1H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoyl]-L-glutamic acid, 2,4-diamino-6-(N-(4-(phenylsulfonyl)benzyl)methylamino)quinazoline, 2,4-diamino-5-[4-[3-(4-aminophenyl-4-sulfonylphenylamino)propoxy]-3,5-dimethoxybenzyl]pyrimidine, N-[4-[4-(2,4-diamino-5-pyrimidinyl)butyl]benzoyl]-L-glutamic acid, N-[4-[3-(2,4-diamino-5-pyrimidinyl)propyl]benzoyl]-L-glutamic acid, N-[4-[2-(2,4-diamino-6-pteridinyl)ethyl]-benzoyl]-4-methylene-DL-glutamic acid and N-(1-methylethyl)-N-[3-(2,4,5-trichlorophenoxy)propoxy]imidodicarbonimidic diamide hydrochloride (PS15).
- 7. The pharmaceutical composition according to claim 3, wherein said compound having a folate antagonist activity or a dihydrofolate reductase inhibiting activity is selected from the group consisting of methotrexate, edatrexate, epiroprim, iometrexol, pyritrexim, trimetrexate, brodimoprim, MX-68, N-[4-[3-(2,4-diamino-6,7-dihydro-5H-cyclopenta[d]-pyrimidin-5-yl)propyl]benzoyl]-L-glutamic acid, N-[[5-[2-(2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido[2,3-d]pyrimidin-6-yl)ethyl]-2-thienyl]carbonyl]-L-glutamic acid, (R)-N-[[5-[2-(2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido[2,3-d]pyrimidin-6-yl)ethyl]-2-thienyl]-carbonyl]-L-glutamic acid, N-((2,4-diamino-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl)ethyl)-2-thienylcarbonyl-L-glutamic acid, (S)-2-[[[4-carboxy-4-[[4-[[(2,4-diamino-6-pteridinyl)methyl]amino]benzoyl]amino]butyl]amino]carbonyl]benzoic acid, N-[4-[3-(2,4-diamino-1H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoyl]-L-glutamic acid, 2,4-diamino-6-(N-(4-(phenylsulfonyl)benzyl)methylamino)quinazoline, 2,4-diamino-5-[4-[3-(4-aminophenyl-4-sulfonylphenylamino)propoxy]-3,5-dimethoxybenzyl]pyrimidine, N-[4-[4-(2,4-diamino-5-pyrimidinyl)butyl]benzoyl]-L-glutamic acid, N-[4-[3-(2,4-diamino-5-pyrimidinyl)propyl]benzoyl]-L-glutamic acid, N-[4-[2-(2,4-diamino-6-pteridinyl)ethyl]-benzoyl]-4-methylene-DL-glutamic acid and N-(1-methylethyl)-N-[3-(2,4,5-trichlorophenoxy)propoxy]imidodicarbonimidic diamide hydrochloride (PS15).
- 8. The pharmaceutical composition according to claim 4, wherein said compound having a folate antagonist activity or a dihydrofolate reductase inhibiting activity is selected from the group consisting of methotrexate, edatrexate, epiroprim, iometrexol, pyritrexim, trimetrexate, brodimoprim, MX-68, N-[4-[3-(2,4-diamino-6,7-dihydro-5H-cyclopenta[d]-pyrimidin-5-yl)propyl]benzoyl]-L-glutamic acid, N-[[5-[2-(2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido[2,3-d]pyrimidin-6-yl)ethyl]-2-thienyl]carbonyl]-L-glutamic acid, (R)-N-[[5-[2-(2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido[2,3-d]pyrimidin-6-yl)ethyl]-2-thienyl]-carbonyl]-L-glutamic acid, N-((2,4-diamino-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl)ethyl)-2-thienylcarbonyl-L-glutamic acid, (S)-2-[[[4-carboxy-4-[[4-[[(2,4-diamino-6-pteridinyl)methyl]amino]benzoyl]amino]butyl]amino]carbonyl]benzoic acid, N-[4-[3-(2,4-diamino-1H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoyl]-L-glutamic acid, 2,4-diamino-6-(N-(4-(phenylsulfonyl)benzyl)methylamino)quinazoline, 2,4-diamino-5-[4-[3-(4-aminophenyl-4-sulfonylphenylamino)propoxy]-3,5-dimethoxybenzyl]pyrimidine, N-[4-[4-(2,4-diamino-5-pyrimidinyl)butyl]benzoyl]-L-glutamic acid, N-[4-[3-(2,4-diamino-5-pyrimidinyl)propyl]benzoyl]-L-glutamic acid, N-[4-[2-(2,4-diamino-6-pteridinyl)ethyl]-benzoyl]-4-methylene-DL-glutamic acid and N-(1-methylethyl)-N-[3-(2,4,5-trichlorophenoxy)propoxy]imidodicarbonimidic diamide hydrochloride (PS15).
- 9. The pharmaceutical composition according to claim 1, wherein said compound having a folate antagonist activity or a dihydrofolate reductase inhibiting activity is methotrexate.
- 10. The pharmaceutical composition according to claim 2, wherein said compound having a folate antagonist activity or a dihydrofolate reductase inhibiting activity is methotrexate.
- 11. The pharmaceutical composition according to claim 3, wherein said compound having a folate antagonist activity or a dihydrofolate reductase inhibiting activity is methotrexate.
- 12. The pharmaceutical composition according to claim 4, wherein said compound having a folate antagonist activity or a dihydrofolate reductase inhibiting activity is methotrexate.
- 13. A pharmaceutical composition in the form of a solution comprising effective amounts of pharmacologically active agents together with a diluent therefor, wherein said pharmacologically active agents comprise:
(a) an anti-human Fas antibody having apoptosis inducing activity selected from the group consisting of a monoclonal antibody CH11 and HFE7A, or a humanized antibody thereof in a concentration of 0.1 to 100 ng/ml; and (b) methotrexate in a concentration of 0.05 to 5 nM, the relative amounts of said active ingredients (a) and (b) being such that they exhibit a synergistic apoptosis inducing activity.
- 14. A method for the prevention or treatment of a disease preventable or treatable by an agent having apoptosis inducing activity, comprising administering to a mammal in need thereof effective amounts of:
(a) an anti-human Fas antibody having an apoptosis inducing activity; and (b) a compound having a folate antagonistic activity or a dihydrofolate reductase inhibiting activity, the relative amounts of the active ingredients (a) and (b) administered being such that they exhibit a synergistic apoptosis inducing activity.
- 15. The method according to claim 14, wherein the mammal is a human.
- 16. The method according to claim 15, wherein said anti-human Fas antibody having apoptosis inducing activity is a monoclonal antibody CH11, HFE7A or a humanized antibody thereof.
- 17. The method according to claim 15, wherein said anti-human Fas antibody having apoptosis inducing activity is a monoclonal antibody CH11 or a humanized antibody thereof.
- 18. The method according to claim 15, wherein said anti-human Fas antibody having apoptosis inducing activity is an anti-human Fas monoclonal antibody HFE7A produced by a mouse-mouse hybridoma HFE7A (FERM BP-5828) or a humanized antibody thereof.
- 19. The method according to claim 15, wherein said compound having a folate antagonist activity or a dihydrofolate reductase inhibiting activity is selected from the group consisting of methotrexate, edatrexate, epiroprim, iometrexol, pyritrexim, trimetrexate, brodimoprim, MX-68, N-[4-[3-(2,4-diamino-6,7-dihydro-5H-cyclopenta[d]-pyrimidin-5-yl)propyl]benzoyl]-L-glutamic acid, N-[[5-[2-(2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido[2,3-d]pyrimidin-6-yl)ethyl]-2-thienyl]carbonyl]-L-glutamic acid, (R)-N-[[5-[2-(2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido[2,3-d]pyrimidin-6-yl)ethyl]-2-thienyl]-carbonyl]-L-glutamic acid, N-((2,4-diamino-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl)ethyl)-2-thienylcarbonyl-L-glutamic acid, (S)-2-[[[4-carboxy-4-[[4-[[(2,4-diamino-6-pteridinyl)methyl]amino]benzoyl]amino]butyl]amino]carbonyl]benzoic acid, N-[4-[3-(2,4-diamino-1H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoyl]-L-glutamic acid, 2,4-diamino-6-(N-(4-(phenylsulfonyl)benzyl)methylamino)quinazoline, 2,4-diamino-5-[4-[3-(4-aminophenyl-4-sulfonylphenylamino)propoxy]-3,5-dimethoxybenzyl]pyrimidine, N-[4-[4-(2,4-diamino-5-pyrimidinyl)butyl]benzoyl]-L-glutamic acid, N-[4-[3-(2,4-diamino-5-pyrimidinyl)propyl]benzoyl]-L-glutamic acid, N-[4-[2-(2,4-diamino-6-pteridinyl)ethyl]-benzoyl]-4-methylene-DL-glutamic acid and N-(1-methylethyl)-N-[3-(2,4,5-trichlorophenoxy)propoxy]imidodicarbonimidic diamide hydrochloride (PS15).
- 20. The method according to claim 16, wherein said compound having a folate antagonist activity or a dihydrofolate reductase inhibiting activity is selected from the group consisting of methotrexate, edatrexate, epiroprim, iometrexol, pyritrexim, trimetrexate, brodimoprim, MX-68, N-[4-[3-(2,4-diamino-6,7-dihydro-5H-cyclopenta[d]-pyrimidin-5-yl)propyl]benzoyl]-L-glutamic acid, N-[[5-[2-(2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido[2,3d]pyrimidin-6-yl)ethyl]-2-thienyl]carbonyl]-L-glutamic acid, (R)-N-[[5-[2-(2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido[2,3-d]pyrimidin-6-yl)ethyl]-2-thienyl]-carbonyl]-L-glutamic acid, N-((2,4-diamino-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl)ethyl)-2-thienylcarbonyl-L-glutamic acid, (S)-2-[[[4-carboxy-4-[[4-[[(2,4-diamino-6-pteridinyl)methyl]amino]benzoyl]amino]butyl]amino]carbonyl]benzoic acid, N-[4-[3-(2,4-diamino-1H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoyl]-L-glutamic acid, 2,4-diamino-6-(N-(4-(phenylsulfonyl)benzyl)methylamino)quinazoline, 2,4-diamino-5-[4-[3-(4-aminophenyl-4-sulfonylphenylamino)propoxy]-3,5-dimethoxybenzyl]pyrimidine, N-[4-[4-(2,4-diamino-5-pyrimidinyl)butyl]benzoyl]-L-glutamic acid, N-[4-[3-(2,4-diamino-5-pyrimidinyl)propyl]benzoyl]-L-glutamic acid, N-[4-[2-(2,4-diamino-6-pteridinyl)ethyl]-benzoyl]-4-methylene-DL-glutamic acid and N-(1-methylethyl)-N-[3-(2,4,5-trichlorophenoxy)propoxylimidodicarbonimidic diamide hydrochloride (PS15).
- 21. The method according to claim 17, wherein said compound having a folate antagonist activity or a dihydrofolate reductase inhibiting activity is selected from the group consisting of methotrexate, edatrexate, epiroprim, iometrexol, pyritrexim, trimetrexate, brodimoprim, MX-68, N-[4-[3-(2,4-diamino-6,7-dihydro-5H-cyclopenta[d]-pyrimidin-5-yl)propyl]benzoyl]-L-glutamic acid, N-[[5-[2-(2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido[2,3-d]pyrimidin-6-yl)ethyl]-2-thienyl]carbonyl]-L-glutamic acid, (R)-N-[[5-[2-(2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido[2,3-d]pyrimidin-6-yl)ethyl]-2-thienyl]-carbonyl]-L-glutamic acid, N-((2,4-diamino-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl)ethyl)-2-thienylcarbonyl-L-glutamic acid, (S)-2-[[[4-carboxy-4-[[4-[[(2,4-diamino-6-pteridinyl)methyl]amino]benzoyl]amino]butyl]amino]carbonyl]benzoic acid, N-[4-[3-(2,4-diamino-1H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoyl]-L-glutamic acid, 2,4-diamino-6-(N-(4-(phenylsulfonyl)benzyl)methylamino)quinazoline, 2,4-diamino-5-[4-[3-(4-aminophenyl-4-sulfonylphenylamino)propoxy]-3,5-dimethoxybenzyl]pyrimidine, N-[4-[4-(2,4-diamino-5-pyrimidinyl)butyl]benzoyl]-L-glutamic acid, N-[4-[3-(2,4-diamino-5-pyrimidinyl)propyl]benzoyl]-L-glutamic acid, N-[4-[2-(2,4-diamino-6-pteridinyl)ethyl]-benzoyl]-4-methylene-DL-glutamic acid and N-(1-methylethyl)-N-[3-(2,4,5-trichlorophenoxy)propoxy]imidodicarbonimidic diamide hydrochloride (PS15).
- 22. The method according to claim 18, wherein said compound having a folate antagonist activity or a dihydrofolate reductase inhibiting activity is selected from the group consisting of methotrexate, edatrexate, epiroprim, iometrexol, pyritrexim, trimetrexate, brodimoprim, MX-68, N-[4-[3-(2,4-diamino-6,7-dihydro-5H-cyclopenta[d]-pyrimidin-5-yl)propyl]benzoyl]-L-glutamic acid, N-[[5-[2-(2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido[2,3-d]pyrimidin-6-yl)ethyl]-2-thienyl]carbonyl]-L-glutamic acid, (R)-N-[[5-[2-(2-amino-1,4,5,6,7,8-hexahydro-4-oxopyrido[2,3-d]pyrimidin-6-yl)ethyl]-2-thienyl]-carbonyl]-L-glutamic acid, N-((2,4-diamino-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl)ethyl)-2-thienylcarbonyl-L-glutamic acid, (S)-2-[[[4-carboxy-4-[[4-[[(2,4-diamino-6-pteridinyl)methyl]amino]benzoyl]amino]butyl]amino]carbonyl]benzoic acid, N-[4-[3-(2,4-diamino-1H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoyl]-L-glutamic acid, 2,4-diamino-6-(N-(4-(phenylsulfonyl)benzyl)methylamino)quinazoline, 2,4-diamino-5-[4-[3-(4-aminophenyl-4-sulfonylphenylamino)propoxy]-3,5-dimethoxybenzyl]pyrimidine, N-[4-[4-(2,4-diamino-5-pyrimidinyl)butyl]benzoyl]-L-glutamic acid, N-[4-[3-(2,4-diamino-5-pyrimidinyl)propyl]benzoyl]-L-glutamic acid, N-[4-[2-(2,4-diamino-6-pteridinyl)ethyl]-benzoyl]-4-methylene-DL-glutamic acid and N-(1-methylethyl)-N-[3-(2,4,5-trichlorophenoxy)propoxy]imidodicarbonimidic diamide hydrochloride (PS15).
- 23. The method according to claim 15, wherein said compound having a folate antagonist activity or a dihydrofolate reductase inhibiting activity is methotrexate.
- 24. The method according to claim 16, wherein said compound having a folate antagonist activity or a dihydrofolate reductase inhibiting activity is methotrexate.
- 25. The method according to claim 17, wherein said compound having a folate antagonist activity or a dihydrofolate reductase inhibiting activity is methotrexate.
- 26. The method according to claim 18, wherein said compound having a folate antagonist activity or a dihydrofolate reductase inhibiting activity is methotrexate.
- 27. The method according to claim 15, wherein the anti-human Fas antibody is administered in a daily dosage of 0.001 to 10 mg/kg and the compound having a folate antagonistic activity or a dihydrofolate reductase inhibiting activity is administered in a daily dosage of 0.15 μg/kg to 0.15 mg/kg.
- 28. A method for the prevention or treatment of a disease preventable or treatable by an agent having apoptosis inducing activity, comprising administering to a mammal in need thereof effective amounts of a medicament in the form of a solution comprising pharmacologically active agents together with a diluent therefor, wherein said pharmacologically active agents comprise:
(a) an anti-human Fas antibody having apoptosis inducing activity selected from the group consisting of a monoclonal antibody CH11 and HFE7A, or a humanized antibody thereof in a concentration of 0.1 to 100 ng/ml; and (b) methotrexate at a concentration of 0.05 to 5 nM, the relative amounts of said active ingredients (a) and (b) being such that they exhibit a synergistic apoptosis inducing activity.
- 29. The method according to claim 28, wherein the mammal is a human.
- 30. The method according to claim 15, wherein said disease is an autoimmune disease or rheumatoid arthritis.
- 31. The method according to claim 16, wherein said disease is an autoimmune disease or rheumatoid arthritis.
- 32. The method according to claim 17, wherein said disease is an autoimmune disease or rheumatoid arthritis.
- 33. The method according to claim 18, wherein said disease is an autoimmune disease or rheumatoid arthritis.
- 34. The method according to claim 19, wherein said disease is an autoimmune disease or rheumatoid arthritis.
- 35. The method according to claim 20, wherein said disease is an autoimmune disease or rheumatoid arthritis.
- 36. The method according to claim 21, wherein said disease is an autoimmune disease or rheumatoid arthritis.
- 37. The method according to claim 22, wherein said disease is an autoimmune disease or rheumatoid arthritis.
- 38. The method according to claim 23, wherein said disease is an autoimmune disease or rheumatoid arthritis.
- 39. The method according to claim 24, wherein said disease is an autoimmune disease or rheumatoid arthritis.
- 40. The method according to claim 25, wherein said disease is an autoimmune disease or rheumatoid arthritis.
- 41. The method according to claim 26, wherein said disease is an autoimmune disease or rheumatoid arthritis.
- 42. The method according to claim 27, wherein said disease is an autoimmune disease or rheumatoid arthritis.
- 43. The method according to claim 28, wherein said disease is an autoimmune disease or rheumatoid arthritis.
Priority Claims (1)
Number |
Date |
Country |
Kind |
11-143033 |
May 1999 |
JP |
|
Parent Case Info
[0001] This application is a continuation-in-part application of international application PCT/JP00/03324 filed May 24, 2000 (not published in English).
Continuation in Parts (1)
|
Number |
Date |
Country |
Parent |
PCT/JP00/03324 |
May 2000 |
US |
Child |
09989620 |
Nov 2001 |
US |