IP Library › Granted Patent US 9,370,584

Granted Patent B2

US 9,370,584 · App. 12/912,107 · Granted Jun 21, 2016

CA6 antigen-specific cytotoxic conjugate and methods of using the same

Inventors: Gillian Payne (Waban, MA); Philip Chun (Malden, MA); Daniel J. Tavares (Natick, MA)

Assignee: IMMUNOGEN INC.

A61K47/48384 A61K47/48407 A61K47/48569 C07K14/4727 C07K14/4748 C07K16/3092 A61K39/39558 A61K2039/505 C07K2317/24 C07K2317/56 C07K2317/565 C07K2317/567 C07K2317/92

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Quick Facts

Patent No.: US 9,370,584
App. No.: 12/912,107
Granted: Jun 21, 2016
Kind: B2

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Abstract

Cytotoxic conjugates comprising a cell binding agent and a cytotoxic agent, therapeutic compositions comprising the conjugate, methods for using the conjugates in the inhibition of cell growth and the treatment of disease, and a kit comprising the cytotoxic conjugate are disclosed are all embodiments of the invention. In particular, the cell binding agent is a monoclonal antibody, and epitope-binding fragments thereof, that recognizes and binds the CA6 glycotope. The present invention is also directed to humanized or resurfaced versions of DS6, an anti-CA6 murine monoclonal antibody, and epitope-binding fragments thereof.

Claims (219)

1. A method of treating a subject having a cancer expressing CA6 glycotope, said method comprising, administering a therapeutically effective amount of a conjugate to said subject, wherein said conjugate comprises a cell binding agent and a cytotoxic agent, wherein said cell binding agent comprises an antibody or epitope-binding fragment thereof comprising at least one heavy chain variable region and at least one light chain variable region, wherein said heavy chain variable region comprises three complementarity-determining regions having amino acids 31-35, 50-66, and 99-106 of SEQ ID NO:11, respectively, and wherein said light chain variable region comprises three sequential complementarity-determining regions having amino acids 24-33, 49-55, and 88-96 of SEQ ID NO:8, respectively, wherein the cell binding agent binds to the CA6 glycotope.

2. A method of treating a subject having a cancer expressing CA6 glycotope, said method comprising, administering a therapeutically effective amount of a conjugate to said subject, wherein said conjugate comprises a cell binding agent and a cytotoxic agent, wherein said cell binding agent comprises an antibody or epitope-binding fragment thereof comprising at least one heavy chain variable region and at least one light chain variable region, wherein said heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:10 or 11, wherein said light chain variable region comprises three sequential complementarity-determining regions comprising the amino acid sequences set forth in SEQ ID NOs:4-6, respectively, and wherein the cell binding agent binds to the CA6 glycotope.

3. A method of treating a subject having a cancer expressing CA6 glycotope, said method comprising, administering a therapeutically effective amount of a conjugate to said subject, wherein said conjugate comprises a cell binding agent and a cytotoxic agent, wherein said cell binding agent comprises an antibody or epitope-binding fragment thereof comprising at least one heavy chain variable region and at least one light chain variable region, wherein said light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:8, wherein said heavy chain variable region comprises three complementarity-determining regions comprising the amino acid sequences set forth in SEQ ID NOS:20-22, respectively, and wherein the cell binding agent binds to the CA6 glycotope.

4. The method of claim 3 , wherein said heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:10 or 11.

5. The method of claim 1 , wherein said antibody or epitope-binding fragment thereof is selected from the group consisting of a Fab fragment, a Fab′ fragment, a F(ab′) 2 fragment, a single-chain Fvs (scFv) fragment, a single-chain antibody, and a disulfide-linked Fvs (sdFv) fragment.

6. The method of claim 1 , wherein said cell binding agent and said cytotoxic agent are covalently linked through a PEG linking group.

7. The method of claim 1 , wherein said cell binding agent and said cytotoxic agent are covalently linked through a thiol or disulfide functionality of said cytotoxic agent.

8. The method of claim 1 , wherein said cytotoxic agent is the maytansinoid compound DM1 of formula (I):

9. The method of claim 1 , wherein said cytotoxic agent is the maytansinoid compound DM4 of formula (II):

10. The method of claim 1 , wherein said cytotoxic agent is the maytansinoid compound of formula (III):

wherein:

Y′ represents

(CR 7 R 8 ) l (CR 9 ═CR 10 ) p (C≡C) q A 0 (CR 5 R 6 ) m D u (CR 11 ≡CR 12 ) r (C≡C) s B t (CR 3 R 4 ) n CR 1 R 2 SZ,

wherein:

R 1 and R 2 are each independently CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical, and in addition R 2 can be H;

A, B, D are cycloalkyl or cycloalkenyl having 3-10 carbon atoms, simple or substituted aryl or heterocyclic aromatic or heterocyclic radical;

R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently H, CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical;

l, m, n, o, p, q, r, s, t, and u are each independently 0 or an integer of from 1 to 5, provided that at least two of l, m, n, o, p, q, r, s t, and u are not zero at any one time; and

Z is H, SR or —COR, wherein R is linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, or simple or substituted aryl or heterocyclic aromatic or heterocyclic radical.

11. The method of claim 10 , wherein R 1 is methyl, R 2 is H and Z is H.

12. The method of claim 10 , wherein R 1 and R 2 are methyl and Z is H.

13. The method of claim 10 , wherein R 1 is methyl, R 2 is H, and Z is —SCH 3 .

14. The method of claim 10 , wherein R 1 and R 2 are methyl, and Z is —SCH 3 .

15. The method of claim 1 , wherein said cytotoxic agent is a maytansinoid compound selected from the group consisting of formulas (IV-L), (IV-D), and (IV-D,L):

wherein:

Y represents (CR 7 R 8 ) l (CR 5 R 6 ) m (CR 3 R 4 ) n CR 1 R 2 SZ,

wherein:

R 1 and R 2 are each independently CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl, or heterocyclic aromatic or heterocyclic radical, and in addition R 2 can be H;

R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently H, CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl, or heterocyclic aromatic or heterocyclic radical;

l, m and n are each independently an integer of from 1 to 5, and in addition n can be 0;

Z is H, SR or —COR wherein R is linear or branched alkyl or alkenyl having from 1 to 10 carbon atoms, cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, or simple or substituted aryl or heterocyclic aromatic or heterocyclic radical; and

May represents a maytansinoid which bears the side chain at C-3, C-14 hydroxymethyl, C-15 hydroxy or C-20 desmethyl.

16. The method of claim 15 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 , and R 8 are each H, l and m are each 1, n is 0, and Z is H.

17. The method of claim 15 , wherein R 1 and R 2 are methyl, R 5 , R 6 , R 7 , R 8 are each H, l and m are 1, n is 0, and Z is H.

18. The method of claim 15 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 , and R 8 are each H, l and m are each 1, n is 0, and Z is —SCH 3 .

19. The method of claim 15 , wherein R 1 and R 2 are methyl, R 5 , R 6 , R 7 , and R 8 are each H, l and m are 1, n is 0, and Z is —SCH 3 .

20. The method of claim 15 , wherein the cytotoxic agent is represented by formula (IV-L).

21. The method of claim 1 , wherein said cytotoxic agent is the maytansinoid compound formula (V):

wherein:

Y represents

(CR 7 R 8 ) l (CR 5 R 6 ) m (CR 3 R 4 ) n CR 1 R 2 SZ,

wherein:

R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 , are each independently H, CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl, or heterocyclic aromatic or heterocyclic radical; and

l, m and n are each independently an integer of from 1 to 5, and in addition n can be 0;

22. The method of claim 21 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 , and R 8 are each H; l and m are each 1; n is 0; and Z is H.

23. The method of claim 21 , wherein R 1 and R 2 are methyl, R 5 , R 6 , R 7 , R 8 are each H, 1 and m are 1; n is 0; and Z is H.

24. The method of claim 21 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 , and R 8 are each H, l and m are each 1, n is 0, and Z is —SCH 3 .

25. The method of claim 21 , wherein R 1 and R 2 are methyl, R 5 , R 6 , R 7 , R 8 are each H, l and m are 1, n is 0, and Z is —SCH 3 .

26. The method of claim 1 , wherein said cytotoxic agent is a maytansinoid compound selected from the group consisting of formulas (VI-L), (VI-D), and (VI-D,L):

wherein:

Y 2 represents

(CR 7 R 8 ) l (CR 5 R 6 ) m (CR 3 R 4 ) n CR 1 R 2 SZ 2 ,

wherein:

R 1 and R 2 are each independently CH 3 , C 2 H 2 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical, and in addition R 2 can be H;

R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 , are each independently H, CH 3 , C 2 H 5 , linear cyclic alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical

l, m and o are each independently an integer of from 1 to 5, and in addition n can be 0;

Z 2 is SR or —COR, wherein R is linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, or simple or substituted aryl or heterocyclic aromatic or heterocyclic radical; and

May is a maytansinoid.

27. The method of claim 1 , wherein said cytotoxic agent is the maytansinoid compound of formula (VII):

or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3-10 carbon atoms, or simple or substituted aryl or heterocyclic aromatic or heterocyclic radical;

wherein:

Y 2 ′ represents

(CR 7 R 8 ) l (CR 9 ═CR 10 ) p (C≡C) q A 0 (CR 5 R 6 ) m D u (CR 11 ═CR 12 ) r (C≡C) s B t (CR 3 R 4 ) n CR 1 R 2 SZ 2 —,

wherein:

R 1 and R 2 are each independently CH 3 , C 2 H 5 , linear branched or alkyl or alkenyl having from 1 to 10 carbon atoms, cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical, and in addition R 2 can be H;

A, B, and D each independently is cycloalkyl or cycloalkenyl having 3 to 10 carbon atoms, simple or substituted aryl, or heterocyclic aromatic or heterocyclic radical;

l, m, n, o, p, q, r, s, t and u are each independently 0 or an integer of from 1 to 5, provided that at least two of l, m, n, o, p, q, r, s t and u are not zero at any one time; and

Z 2 is SR or —COR, wherein R is linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3-10 carbon atoms, or simple or substituted aryl or heterocyclic aromatic or heterocyclic radical.

28. The method of claim 27 , wherein R 1 is methyl and R 2 is H.

29. The method of claim 1 , wherein said cytotoxic agent is the maytansinoid compound of formula (VIII):

wherein:

Y 1 ′ represents

(CR 7 R 8 ) l (CR 9 ═CR 10 ) p (C≡C) q A 0 (CR 5 R 6 ) m D u (CR 11 ═CR 12 ) r (C≡C) s B t (CR 3 R 4 ) n CR 1 R 2 S—,

wherein:

A, B, and D, each independently is cycloalkyl or cycloalkenyl having 3-10 carbon atoms, simple or substituted aryl, or heterocyclic aromatic or heterocyclic radical;

R 1 is methyl and R 2 is H or R 1 and R 2 are methyl;

l, m, n, o, p, q, r, s, t, and u are each independently 0 or an integer of from 1 to 5, provided that at least two of l, m, n, o, p, q, r, s t, and u are not zero at any one time.

30. The method of claim 29 , wherein R 1 is methyl and R 2 is H.

31. The method of claim 29 , wherein R 1 and R 2 are methyl.

32. The method of claim 1 , wherein said cytotoxic agent is a maytansinoid compound selected from the group consisting of formulas (IX-L), (IX-D), and (IX-D,L):

wherein:

Y 1 represents (CR 7 R 8 ) l (CR 5 R 6 ) m (CR 3 R 4 ) n CR 1 R 2 S—, wherein:

R 1 and R 2 are each independently CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl, heterocyclic aromatic or heterocyclic radical, and in addition R 2 can be H;

l, m and n are each independently an integer of from 1 to 5, and in addition n can be 0; and

May represents a maytansinol which bears the side chain at C-3, C-14 hydroxymethyl, C-15 hydroxy or C-20 desmethyl.

33. The method of claim 32 , wherein R 1 is methyl and R 2 is H or R 1 and R 2 are methyl.

34. The method of claim 32 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 and R 8 are each H; l and m are each 1; n is 0.

35. The method of claim 32 , wherein R 1 and R 2 are methyl, R 5 , R 6 , R 7 , R 8 are each H, l and m are 1, n is 0.

36. The method of claim 33 , wherein the maytansinoid is represented by formula (IX-L).

37. The method of claim 34 , wherein the maytansinoid is represented by formula (IX-L).

38. The method of claim 35 , wherein the maytansinoid is represented by formula (IX-L).

39. The method of claim 1 , wherein said cytotoxic agent is the maytansinoid compound of formula (X):

wherein:

Y 1 represents (CR 7 R 8 ) l (CR 5 R 6 ) m (CR 3 R 4 ) n CR 1 R 2 S—,

wherein:

R 1 and R 2 are each independently CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl, heterocyclic aromatic or heterocyclic radical, and in addition R 2 can be H;

R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently H, CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocyclic radical;

l, m and n are each independently an integer of from 1 to 5, and in addition n can be 0; and

May represents a maytansinol which bears the side chain at C-3, C-14 hydroxymethyl, C-15 hydroxy or C-20 desmethyl.

40. The method of claim 39 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 , and R 8 are each H, l and m are 1, and n is 0.

41. The method of claim 39 , wherein R 1 and R 2 are methyl, R 5 , R 6 , R 7 , and R 8 are each H, l and m are 1, and n is 0.

42. The method of claim 1 , wherein said cytotoxic agent is DM1 or DM4.

43. The method of claim 1 , wherein said cytotoxic agent is the taxane formula (XI):

44. The method of claim 1 , wherein said cytotoxic agent is member selected from the group consisting of a maytansinoid compound, a taxoid compound, a CC-1065 compound, a dolastatin compound, a daunorubicin compound, and a doxorubicin compound.

45. The method of claim 1 , wherein said cell binding agent and said cytotoxic agent are covalently linked via a N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB) linker, wherein said cytotoxic agent is DM4.

46. The method of claim 45 , wherein 1-10 DM4 molecules are linked to said cell binding agent.

47. The method of claim 4 , wherein said antibody or epitope-binding fragment thereof is selected from the group consisting of a Fab fragment, a Fab′ fragment, a F(ab′) 2 fragment, a single-chain Fvs (scFv) fragment, a single-chain antibody, and a disulfide-linked Fvs (sdFv) fragment.

48. The method of claim 4 , wherein said cell binding agent and said cytotoxic agent are covalently linked through a PEG linking group.

49. The method of claim 4 , wherein said cell binding agent and said cytotoxic agent are covalently linked through a thiol or disulfide functionality of said cytotoxic agent.

50. The method of claim 4 , wherein said cytotoxic agent is the maytansinoid compound DM1 of formula (I):

51. The method of claim 4 , wherein said cytotoxic agent is the maytansinoid compound DM4 of formula (II):

52. The method of claim 4 , wherein said cytotoxic agent is the maytansinoid compound of formula (III):

wherein:

Y′ represents

(CR 7 R 5 ) l (CR 9 ═CR 10 ) p (C≡C) q A 0 (CR 5 R 6 ) m D u (CR 11 ═CR 12 ) r (C≡C) s B t (CR 3 R 4 ) n CR 1 R 2 SZ,

wherein:

A, B, D are cycloalkyl or cycloalkenyl having 3-10 carbon atoms, simple or substituted aryl or heterocyclic aromatic or heterocyclic radical;

l, m, n, o, p, q, r, s, t, and u are each independently 0 or an integer of from 1 to 5, provided that at least two of l, m, n, o, p, q, r, s t, and u are not zero at any one time; and

53. The method of claim 52 , wherein R 1 is methyl, R 2 is H and Z is H.

54. The method of claim 52 , wherein R 1 and R 2 are methyl and Z is H.

55. The method of claim 52 , wherein R 1 is methyl, R 2 is H, and Z is —SCH 3 .

56. The method of claim 52 , wherein R 1 and R 2 are methyl, and Z is —SCH 3 .

57. The method of claim 4 , wherein said cytotoxic agent is a maytansinoid compound selected from the group consisting of formulas (IV-L), (IV-D), and (IV-D,L):

wherein:

Y represents (CR 7 R 8 ) l (CR 5 R 6 ) m (CR 3 R 4 ) n CR 1 R 2 SZ,

wherein:

R 1 and R 2 are each independently CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl, or heterocyclic aromatic or heterocyclic radical, and in addition R 2 can be H;

l, m and n are each independently an integer of from 1 to 5, and in addition n can be 0;

May represents a maytansinoid which bears the side chain at C-3, C-14 hydroxymethyl, C-15 hydroxy or C-20 desmethyl.

58. The method of claim 57 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 , and R 8 are each H, l and m are each 1, n is 0, and Z is H.

59. The method of claim 57 , wherein R 1 and R 2 are methyl, R 5 , R 6 , R 7 , R 8 are each H, l and m are 1, n is 0, and Z is H.

60. The method of claim 57 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 , and R 8 are each H, l and m are each 1, n is 0, and Z is —SCH 3 .

61. The method of claim 57 , wherein R 1 and R 2 are methyl, R 5 , R 6 , R 7 , and R 8 are each H, l and m are 1, n is 0, and Z is —SCH 3 .

62. The method of claim 57 , wherein the cytotoxic agent is represented by formula (IV-L).

63. The method of claim 4 , wherein said cytotoxic agent is the maytansinoid compound formula (V):

wherein:

Y represents

(CR 7 R 8 ) l (CR 5 R 6 ) m (CR 3 R 4 ) n CR 1 R 2 SZ, wherein:

l, m and n are each independently an integer of from 1 to 5, and in addition n can be 0;

64. The method of claim 63 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 , and R 8 are each H; l and m are each 1; n is 0; and Z is H.

65. The method of claim 63 , wherein R 1 and R 2 are methyl, R 5 , R 6 , R 7 , R 8 are each H, 1 and m are 1; n is 0; and Z is H.

66. The method of claim 63 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 , and R 8 are each H, l and m are each 1, n is 0, and Z is —SCH 3 .

67. The method of claim 63 , wherein R 1 and R 2 are methyl, R 5 , R 6 , R 7 , R 8 are each H, l and m are 1, n is 0, and Z is —SCH 3 .

68. The method of claim 4 , wherein said cytotoxic agent is a maytansinoid compound selected from the group consisting of formulas (VI-L), (VI-D), and (VI-D,L):

wherein:

Y 2 represents

(CR 7 R 8 ) l (CR 5 R 6 ) m (CR 3 R 4 ) n CR 1 R 2 SZ 2 ,

wherein:

l, m and o are each independently an integer of from 1 to 5, and in addition n can be 0;

May is a maytansinoid.

69. The method of claim 4 , wherein said cytotoxic agent is the maytansinoid compound of formula (VII):

or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3-10 carbon atoms, or simple or substituted aryl or heterocyclic aromatic or heterocyclic radical;

wherein:

Y 2 ′ represents

(CR 7 R 8 ) l (CR 9 ═CR 10 ) p (CC) q A 0 (CR 5 R 6 ) m D u (CR 11 ═CR 12 ) r (C≡C) s B t (CR 3 R 4 ) n CR 1 R 2 SZ 2 —,

wherein:

A, B, and D each independently is cycloalkyl or cycloalkenyl having 3 to 10 carbon atoms, simple or substituted aryl, or heterocyclic aromatic or heterocyclic radical;

l, m, n, o, p, q, r, s, t and u are each independently 0 or an integer of from 1 to 5, provided that at least two of l, m, n, o, p, q, r, s t and u are not zero at any one time; and

70. The method of claim 69 , wherein R 1 is methyl and R 2 is H.

71. The method of claim 4 , wherein said cytotoxic agent is the maytansinoid compound of formula (VIII):

wherein:

Y 1 ′ represents

(CR 7 R 8 ) l (CR 9 ═CR 10 ) p (C≡C) q A 0 (CR 5 R 6 ) m D u (CR 11 ═CR 12 ) r (C≡C) s B t (CR 3 R 4 ) n CR 1 R 2 S—,

wherein:

A, B, and D, each independently is cycloalkyl or cycloalkenyl having 3-10 carbon atoms, simple or substituted aryl, or heterocyclic aromatic or heterocyclic radical;

R 1 is methyl and R 2 is H or R 1 and R 2 are methyl;

l, m, n, o, p, q, r, s, t, and u are each independently 0 or an integer of from 1 to 5, provided that at least two of l, m, n, o, p, q, r, s t, and u are not zero at any one time.

72. The method of claim 71 , wherein R 1 is methyl and R 2 is H.

73. The method of claim 71 , wherein R 1 and R 2 are methyl.

74. The method of claim 4 , wherein said cytotoxic agent is a maytansinoid compound selected from the group consisting of formulas (IX-L), (IX-D), and (IX-D,L):

wherein:

Y 1 represents (CR 7 R 8 ) l (CR 5 R 6 ) m (CR 3 R 4 ) n CR 1 R 2 S—, wherein:

R 1 and R 2 are each independently CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl, heterocyclic aromatic or heterocyclic radical, and in addition R 2 can be H;

l, m and n are each independently an integer of from 1 to 5, and in addition n can be 0; and

May represents a maytansinol which bears the side chain at C-3, C-14 hydroxymethyl, C-15 hydroxy or C-20 desmethyl.

75. The method of claim 74 , wherein R 1 is methyl and R 2 is H or R 1 and R 2 are methyl.

76. The method of claim 74 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 and R 8 are each H; l and m are each 1; n is 0.

77. The method of claim 74 , wherein R 1 and R 2 are methyl, R 5 , R 6 , R 7 , R 8 are each H, l and m are 1, n is 0.

78. The method of claim 75 , wherein the maytansinoid is represented by formula (IX-L).

79. The method of claim 76 , wherein the maytansinoid is represented by formula (IX-L).

80. The method of claim 77 , wherein the maytansinoid is represented by formula (IX-L).

81. The method of claim 4 , wherein said cytotoxic agent is the maytansinoid compound of formula (X):

wherein:

Y 1 represents (CR 7 R 8 ) l (CR 5 R 6 ) m CR 3 R 4 ) n CR 1 R 2 S—,

wherein:

R 1 and R 2 are each independently CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl, heterocyclic aromatic or heterocyclic radical, and in addition R 2 can be H;

l, m and n are each independently an integer of from 1 to 5, and in addition n can be 0; and

May represents a maytansinol which bears the side chain at C-3, C-14 hydroxymethyl, C-15 hydroxy or C-20 desmethyl.

82. The method of claim 81 , wherein R 1 is methyl, R 2 is H, R 5 , R 6 , R 7 , and R 8 are each H, l and m are 1, and n is 0.

83. The method of claim 81 , wherein R 1 and R 2 are methyl, R 5 , R 6 , R 7 , and R 8 are each H, l and m are 1, and n is 0.

84. The method of claim 4 , wherein said cytotoxic agent is DM1 or DM4.

85. The method of claim 4 , wherein said cytotoxic agent is the taxane formula (XI):

86. The method of claim 4 , wherein said cytotoxic agent is a member selected from the group consisting of a maytansinoid compound, a taxoid compound, a CC-1065 compound, a dolastatin compound, a daunorubicin compound, and a doxorubicin compound.

87. The method of claim 4 , wherein said cell binding agent and said cytotoxic agent are covalently linked via a N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB) linker, wherein said cytotoxic agent is DM4.

88. The method of claim 87 , wherein 1-10 DM4 molecules are linked to said cell binding agent.

89. The method of claim 1 , wherein the cancer is selected from the group consisting of serous ovarian carcinoma, endometrioid ovarian carcinoma, neoplasm of the uterine cervix, neoplasm of the endometrius, neoplasm of the vulva, breast carcinoma, pancreatic tumor, and tumor of the urothelium.

90. The method of claim 4 , wherein the cancer is selected from the group consisting of serous ovarian carcinoma, endometrioid ovarian carcinoma, neoplasm of the uterine cervix, neoplasm of the endometrius, neoplasm of the vulva, breast carcinoma, pancreatic tumor, and tumor of the urothelium.

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 13, 2017

From: IMMUNOGEN, INC.

To: SANOFI

Reel/Frame 043860/0371 →

CHANGE OF ADDRESS Recorded Oct 21, 2016

From: IMMUNOGEN, INC.

To: IMMUNOGEN, INC.

Reel/Frame 040465/0576 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 22, 2016

From: PAYNE, GILLIAN; TAVARES, DANIEL J.

To: IMMUNOGEN INC.

Reel/Frame 038062/0585 →

Continuity (4)

Division 11213046 · Aug 29, 2005

Continuation In Part 10895135 · Jul 21, 2004

Provisional Application 60488477 · Jul 21, 2003

Related Publication 20110064733A1 · Mar 17, 2011