Combinations of SAP depleting agents and anti-SAP antibodies

1. A method of treating an amyloid disease or disorder in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound which depletes circulating serum amyloid P component (SAP) in the patient and a therapeutically effective amount of an anti-SAP antibody or an antigen binding fragment thereof, wherein said antibody or said binding fragment binds to human SAP bound to amyloid in vivo in its ligand-bound conformation.

2. The method of claim 1 , wherein administration of the compound and antibody or binding fragment is sequential, simultaneous or simultaneous separate.

3. A method of treating an amyloid disease or disorder in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound which depletes circulating serum amyloid P component (SAP) in the patient and a therapeutically effective amount of an anti-SAP antibody or an antigen binding fragment thereof, wherein said antibody or binding fragment binds to human SAP and, wherein the antibody is selected from the group consisting of SAP-5 and Abp1.

4. A method of treating an amyloid disease or disorder in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound which depletes circulating serum amyloid P component (SAP) in the patient and a therapeutically effective amount of an anti-SAP antibody or an antigen binding fragment thereof, wherein said antibody or binding fragment binds to human SAP and, wherein the antibody is SAP-5.

5. A method of treating an amyloid disease or disorder in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound which depletes circulating serum amyloid P component (SAP) in the patient and a therapeutically effective amount of an anti-SAP antibody or an antigen binding fragment thereof, wherein said antibody or binding fragment binds to human SAP and, wherein the antibody is Abp1.

6. The method of claim 1 , wherein said antibody or said binding fragment thereof is humanized.

7. The method of claim 1 , wherein the compound is a D-proline of the Formula:

wherein

R is

and the group

R 1 is hydrogen or halogen;

X—Y—X′ is a linker having from 4 to 20 linear or straight-chain carbon atoms, wherein

X is —(CH 2 ) n —; —CH(R 2 )(CH 2 ) n —; CH 2 O(CH 2 ) n —; CH 2 NH—; benzyl, —C(R 2 )═CH—; —CH 2 CH(OH)—; or thiazol-2,5-diyl; O;

Y is —S—S—; —(CH 2 ) n —; —O—; —NH—; —N(R 2 )—; —CH═CH—; —NHC(O)NH—; —N(R 2 )C(O)N(R 2 )—; —N[CH 2 C 6 H 3 (OCH 3 ) 2 ]—; —N(CH 2 C 6 H 5 )—; —N(CH 2 C 6 H 5 )C(O)N(CH 2 C 6 H 5 )—; —N(alkoxyalkyl)-; N(cycloalkyl-methyl)-; 2,6-pyridyl; 2,5-furanyl; 2,5-thienyl; 1,2-cyclohexyl; 1,3-cyclohexyl; 1,4-cyclohexyl; 1,2-naphthyl; 1,4-naphthyl; 1,5-naphthyl; 1,6-naphthyl; biphenylen; or 1,2-phenylen, 1,3-phenylen and 1,4-phenylen, wherein the phenylen groups are optionally substituted by 1-4 substituents, selected from halogen, lower alkyl, lower alkoxy, hydroxyl, carboxy, —COO-lower alkyl, nitrilo, 5-tetrazol, (2-carboxylic acid pyrrolidin- 1-yl)-2-oxo-ethoxy, N-hydroxycarbamimiodyl, 5-oxo[1,2,4]oxadiazolyl, 2-oxo [1,2,3,5] oxathiadiazolyl, 5-thioxo[1,2,4]oxadiazolyl and 5-tert-butylsulfanyl-[1,2,4]oxadiazolyl;

X′ is —(CH 2 ) n —; —(CH 2 ) n CH(R 2 )—; —(CH 2 ) n OCH 2 —; —NHCH 2 —; benzyl, —CH═C(R 2 )—; CH(OH)CH 2 ; or thiazol-2,5-diyl; O;

R 2 is lower alkyl, lower alkoxy or benzyl and

n is 0-3,

or a pharmaceutically acceptable salt or mono- or diester thereof.

8. The method of claim 7 , wherein the compound is (R)-1-[6-[(R)-2-Carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC).

9. The method of claim 1 wherein said amyloid disease or disorder is selected from the group consisting of any form of systemic or local amyloidosis, type 2 diabetes and Alzheimer's disease.

10. The method of claim 1 wherein the antibody or binding fragment is a monoclonal antibody.

11. The method of claim 1 , wherein the antibody or binding fragment binds to an epitope on human SAP which is the same as an epitope to which SAP-5 or Abp1 binds on human SAP.

12. A method of treating an amyloid disease or disorder in a patient in need of such treatment comprising depleting circulating serum amyloid P component (SAP) in the patient, wherein the improvement comprises administering to the patient a therapeutically effective amount of an anti-SAP antibody or an antigen binding fragment thereof, wherein said antibody or binding fragment binds to human SAP bound to amyloid in vivo in its ligand-bound conformation.

13. The method of claim 12 , wherein said antibody or said binding fragment is humanized.

14. The method of claim 12 , wherein said antibody or binding fragment is a monoclonal antibody.

15. The method of claim 12 wherein said amyloid disease or disorder is selected from the group consisting of any form of systemic or local amyloidosis, type 2 diabetes and Alzheimer's disease.

16. The method of claim 12 , wherein the antibody or binding fragment binds to an epitope on human SAP which is the same as an epitope to which SAP-5 or Abp1 binds on human SAP.

17. A method of treating an amyloid disease or disorder in a patient in need of such treatment, comprising initially administering to the patient a therapeutically effective amount of a compound which depletes circulating serum amyloid P component (SAP) in the patient and thereafter administering a therapeutically effective amount of an anti-SAP antibody or an antigen binding fragment thereof, wherein said antibody or said binding fragment binds to human SAP bound to amyloid in vivo in its ligand-bound conformation.

18. The method of claim 17 , wherein the compound is a D-proline of the Formula:

wherein

R is

and the group

R 1 is hydrogen or halogen;

X—Y—X′ is a linker having from 4 to 20 linear or straight-chain carbon atoms, wherein

X is —(CH 2 ) n —; —CH(R 2 )(CH 2 ) n —; CH 2 O(CH 2 ) n —; CH 2 NH—; benzyl, —C(R 2 )═CH—; —CH 2 CH(OH)—; or thiazol-2,5-diyl; O;

Y is —S—S—; —(CH 2 ) n —; —O—; —NH—; —N(R 2 )—; —CH═CH—; —NHC(O)NH—; —N(R 2 )C(O)N(R 2 )—; —N[CH 2 C 6 H 3 (OCH 3 ) 2 ]—; —N(CH 2 C 6 H 5 )—; —N(CH 2 C 6 H 5 )C(O)N(CH 2 C 6 H 5 )—; —N(alkoxyalkyl)-; N(cycloalkyl-methyl)-; 2,6-pyridyl; 2,5-furanyl; 2,5-thienyl; 1,2-cyclohexyl; 1,3-cyclohexyl; 1,4-cyclohexyl; 1,2-naphthyl; 1,4-naphthyl; 1,5-naphthyl; 1,6-naphthyl; biphenylen; or 1,2-phenylen, 1,3-phenylen and 1,4-phenylen, wherein the phenylen groups are optionally substituted by 1-4 substituents, selected from halogen, lower alkyl, lower alkoxy, hydroxyl, carboxy, —COO-lower alkyl, nitrilo, 5-tetrazol, (2-carboxylic acid pyrrolidin-1-yl)-2-oxo-ethoxy, N-hydroxycarbamimiodyl, 5-oxo[1,2,4]oxadiazolyl, 2-oxo [1,2,3,5]oxathiadiazolyl, 5-thioxo[1,2,4]oxadiazolyl and 5-tert-butylsulfanyl-[1,2,4]oxadiazolyl;

X′ is —(CH 2 ) n —; —(CH 2 ) n CH(R 2 )—; —(CH 2 ) n OCH 2 —; —NHCH 2 —; benzyl, —CH═C(R 2 )—; CH(OH)CH 2 ; or thiazol-2,5-diyl; O;

R 2 is lower alkyl, lower alkoxy or benzyl and

n is 0-3,

or a pharmaceutically acceptable salt or mono- or diester thereof.

19. The method of claim 18 , wherein the compound is (R)-1-[6-[(R)-2-Carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC).

20. The method of claim 17 , wherein said antibody or said binding fragment is humanized.

21. The method of claim 17 , wherein said antibody or binding fragment is a monoclonal antibody.

22. The method of claim 17 , wherein said amyloid disease or disorder is selected from the group consisting of any form of systemic or local amyloidosis, type 2 diabetes and Alzheimer's disease.

23. The method of claim 17 , wherein the antibody or binding fragment binds to an epitope on human SAP which is the same as an epitope to which SAP-5 or Abp1 binds on human SAP.

24. The method of any one of claim 1 , 12 or 17 wherein the antibody or binding fragment binds to a linear epitope or a conformational epitope on human SAP bound to amyloid in vivo.

25. The method of claim 24 wherein the linear epitope is within amino acids 1-159 of human SAP (SEQ ID NO: 1).

26. The method of claim 25 wherein the epitope includes amino acids within residues 140-159 of human SAP (SEQ ID NO: 1).

27. The method of any one of claim 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 11 , 12 , 13 , 15 , 16 , 17 , 18 , 19 , 20 , 22 , or 23 wherein the antibody or binding fragment is an antibody.

28. The method of claim 24 wherein the antibody or binding fragment is an antibody.

29. The method of claim 25 wherein the antibody or binding fragment is an antibody.

30. The method of claim 26 wherein the antibody or binding fragment is an antibody.

31. The method of any one of claim 11 , 16 or 23 wherein the epitope is an epitope to which SAP-5 binds.

32. The method of any one of claim 11 , 16 or 23 wherein the epitope is an epitope to which Abp-1 binds.

33. The method of claim 31 wherein the antibody or binding fragment is an antibody.

34. The method of claim 32 wherein the antibody or binding fragment is an antibody.

35. The method of any one of claim 2 , 3 , 4 , 5 , 6 , 9 , 11 , 12 , 13 , 15 , 16 , 20 , 22 , or 23 wherein the administering of the compound comprises administering a D-proline compound of the Formula:

wherein

R is

and the group

R 1 is hydrogen or halogen;

X—Y—X′ is a linker having from 4 to 20 linear or straight-chain carbon atoms, wherein

X is —(CH 2 ) n —; —CH(R 2 )(CH 2 ) n —; CH 2 O(CH 2 ) n —; CH 2 NH—; benzyl, —C(R 2 )═CH—; —CH 2 CH(OH)—; or thiazol-2,5-diyl; O;

Y is —S—S—; —(CH 2 ) n —; —O—; —NH—; —N(R 2 )—; —CH═CH—; —NHC(O)NH—; —N(R 2 )C(O)N(R 2 )—; —N[CH 2 C 6 H 3 (OCH 3 ) 2 ]—; —N(CH 2 C 6 H 5 )—; —N(CH 2 C 6 H 5 )C(O)N(CH 2 C 6 H 5 )—; —N(alkoxyalkyl)-; N(cycloalkyl-methyl)-; 2,6-pyridyl; 2,5-furanyl; 2,5-thienyl; 1,2-cyclohexyl; 1,3-cyclohexyl; 1,4-cyclohexyl; 1,2-naphthyl; 1,4-naphthyl; 1,5-naphthyl; 1,6-naphthyl; biphenylen; or 1,2-phenylen, 1,3-phenylen and 1,4-phenylen, wherein the phenylen groups are optionally substituted by 1-4 substituents, selected from halogen, lower alkyl, lower alkoxy, hydroxyl, carboxy, —COO-lower alkyl, nitrilo, 5-tetrazol, (2-carboxylic acid pyrrolidin-1-yl)-2-oxo-ethoxy, N-hydroxycarbamimiodyl, 5-oxo[1,2,4]oxadiazolyl, 2-oxo [1,2,3,5] oxathiadiazolyl, 5-thioxo[1,2,4]oxadiazolyl and 5-tert-butylsulfanyl-[1,2,4]oxadiazolyl;

X′ is —(CH 2 ) n —; —(CH 2 ) n CH(R 2 )—; —(CH 2 ) n OCH 2 —; —NHCH 2 —; benzyl, —CH═C(R 2 )—; CH(OH)CH 2 ; or thiazol-2,5-diyl; O;

R 2 is lower alkyl, lower alkoxy or benzyl and

n is 0-3,

or a pharmaceutically acceptable salt or mono- or diester thereof.

36. The method of claim 35 wherein the compound is (R)-1-[6-[(R)-2-Carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC).

37. The method of claim 35 wherein the antibody or binding fragment is an antibody.

38. The method of claim 36 wherein the antibody or binding fragment is an antibody.

39. The method of any one of claim 10 , 14 or 21 wherein the administering of the compound comprises administering a D-proline compound of the Formula:

wherein

R is

and the group

R 1 is hydrogen or halogen;

X—Y—X′ is a linker having from 4 to 20 linear or straight-chain carbon atoms, wherein

X is —(CH 2 ) n —; —CH(R 2 )(CH 2 ) n —; CH 2 O(CH 2 ) n —; CH 2 NH—; benzyl, —C(R 2 )═CH—; —CH 2 CH(OH)—; or thiazol-2,5-diyl; O;

Y is —S—S—; —(CH 2 ) n —; —O—; —NH—; —N(R 2 )—; —CH═CH—; —NHC(O)NH—; —N(R 2 )C(O)N(R 2 )—; —N[CH 2 C 6 H 3 (OCH 3 ) 2 ]—; —N(CH 2 C 6 H 5 )—; —N(CH 2 C 6 H 5 )C(O)N(CH 2 C 6 H 5 )—; —N(alkoxyalkyl)-; N(cycloalkyl-methyl)-; 2,6-pyridyl; 2,5-furanyl; 2,5-thienyl; 1,2-cyclohexyl; 1,3-cyclohexyl; 1,4-cyclohexyl; 1,2-naphthyl; 1,4-naphthyl; 1,5-naphthyl; 1,6-naphthyl; biphenylen; or 1,2-phenylen, 1,3-phenylen and 1,4-phenylen, wherein the phenylen groups are optionally substituted by 1-4 substituents, selected from halogen, lower alkyl, lower alkoxy, hydroxyl, carboxy, —COO-lower alkyl, nitrilo, 5-tetrazol, (2-carboxylic acid pyrrolidin-1-yl)-2-oxo-ethoxy, N-hydroxycarbamimiodyl, 5-oxo[1,2,4]oxadiazolyl, 2-oxo [1,2,3,5]oxathiadiazolyl, 5-thioxo[1,2,4]oxadiazolyl and 5-tert-butylsulfanyl-[1,2,4]oxadiazolyl;

X′ is —(CH 2 ) n —; —(CH 2 ) n CH(R 2 )—; —(CH 2 ) n OCH 2 —; —NHCH 2 —; benzyl, —CH═C(R 2 )—; CH(OH)CH 2 ; or thiazol-2,5-diyl; O;

R 2 is lower alkyl, lower alkoxy or benzyl and

n is 0-3,

or a pharmaceutically acceptable salt or mono- or diester thereof.

40. The method of claim 39 wherein the compound is (R)-1-[6-[(R)-2-Carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC).

41. An anti-serum amyloid P component (SAP) antibody or an antigen binding fragment thereof, wherein said antibody or binding fragment binds to human SAP and, wherein the antibody is Abp1.

42. The antibody or binding fragment of claim 41 which is an antibody.