Anti-DLL3 antibody drug conjugates

Patent metadata

Field	Value
Publication number	US-9968687-B2
Application number	US-201414769787-A
Country	US
Kind code	B2
Filing date	Feb 21, 2014
Priority date	Feb 22, 2013
Publication date	May 15, 2018
Grant date	May 15, 2018

Abstract

Provided are novel antibody drug conjugates (ADCs), and methods of using such ADCs to treat proliferative disorders.

First claim

The invention claimed is:

1. An antibody drug conjugate (ADC) comprising an anti-DLL3 antibody covalently linked through a linker to one or more pyrrolobenzodiazepines (PBDs), wherein the one or more PBDs is/are

2. The antibody drug conjugate of claim 1 , wherein the linker comprises a cleavable linker.

3. The antibody drug conjugate of claim 2 , wherein the cleavable linker comprises a peptidyl linker comprising at least two amino acids.

4. The antibody drug conjugate of claim 3 , wherein the peptidyl linker comprises a valine-alanine dipeptide.

5. The antibody drug conjugate of claim 4 comprising the structure:

wherein the asterisk indicates the point of attachment to the one or more PBDs, and wherein the wavy line indicates the point of attachment to the remaining portion of the linker.

6. The antibody drug conjugate of claim 5 , wherein the linker further comprises a maleimide group.

7. The antibody drug conjugate of claim 1 , wherein the anti-DLL3 antibody is covalently linked to more than one PBD.

8. The antibody drug conjugate of claim 1 , wherein the ADC has a drug loading of 2.

9. The antibody drug conjugate of claim 1 , wherein 1 to 8 PBDs are covalently attached to the anti-DLL3 antibody.

10. The antibody drug conjugate according to claim 1 , wherein the antibody drug conjugate comprises

wherein Ab comprises the anti-DLL3 antibody.

11. The antibody drug conjugate according to claim 10 , wherein Ab is covalently linked to more than one PBD.

12. The antibody drug conjugate according to claim 10 , wherein the ADC has a drug loading of 2.

13. The antibody drug conjugate according to claim 10 , wherein 1 to 8 PBDs are covalently attached to Ab.

14. The antibody drug conjugate of claim 1 , wherein the anti-DLL3 antibody is selected from the group consisting of monoclonal antibody, chimeric antibody, CDR-grafted antibody, humanized antibody, human antibody, primatized antibody, multispecific antibody, bispecific antibody, monovalent antibody, multivalent antibody, diabody, Fab fragment, F(ab′) 2 fragment, Fv fragment, and ScFv fragment; or an immunoreactive fragment thereof.

15. The antibody drug conjugate of claim 1 , wherein the anti-DLL3 antibody is an internalizing antibody.

16. The antibody drug conjugate of claim 1 , wherein the anti-DLL3 antibody specifically binds to an epitope within the DSL domain of a DLL3 protein set forth as SEQ ID NO: 1 or 2.

17. The antibody drug conjugate of claim 16 , wherein the anti-DLL3 antibody specifically binds to an epitope comprising amino acids G203, R205, and P206 (SEQ ID NO:4).

18. The antibody drug conjugate of claim 1 , wherein the anti-DLL3 antibody competes for binding to a human DLL3 protein with an antibody comprising a light chain variable region set forth as SEQ ID NO: 405 and a heavy chain variable region set forth as SEQ ID NO: 407.

19. The antibody drug conjugate of claim 18 , wherein the anti-DLL3 antibody comprises three CDRs of a light chain variable region set forth as SEQ ID NO: 405 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 407.

20. The antibody drug conjugate of claim 19 , wherein the anti-DLL3 antibody comprises residues 24-34 of SEQ ID NO: 405 for CDR-L1, residues 50-56 of SEQ ID NO: 405 for CDR-L2, residues 89-97 of SEQ ID NO: 405 for CDR-L3, residues 31-35 of SEQ ID NO: 407 for CDR-H1, residues 50-65 of SEQ ID NO: 407 for CDR-H2, and residues 95-102 of SEQ ID NO: 407 for CDR-H3, wherein the residues are numbered according to Kabat.

21. The antibody drug conjugate of claim 18 , wherein the anti-DLL3 antibody comprises a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 405 and a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 407.

22. A pharmaceutical composition comprising (a) the antibody drug conjugate of claim 1 , and (b) a pharmaceutically acceptable carrier.

23. The pharmaceutical composition of claim 22 comprising a drug to antibody ratio (DAR) of 1, 2, 3, 4, 5, 6, 7 or 8 each +/−0.4.

24. The pharmaceutical composition of claim 23 comprising a DAR of 2+/−0.4.

25. The pharmaceutical composition of claim 24 comprising less than 30% of non-predominant ADC species.

26. An antibody drug conjugate (ADC) comprising an anti-DLL3 antibody covalently linked through a linker to one or more pyrrolobenzodiazepines (PBDs),
wherein the anti-DLL3 antibody comprises three CDRs of a light chain variable region set forth as SEQ ID NO: 405 and three CDRs of a heavy chain variable region set forth as SEQ ID NO: 407; and
wherein the one or more PBDs is/are:

27. The antibody drug conjugate of claim 26 , wherein the anti-DLL3 antibody comprises residues 24-34 of SEQ ID NO: 405 for CDR-L1, residues 50-56 of SEQ ID NO: 405 for CDR-L2, residues 89-97 of SEQ ID NO: 405 for CDR-L3, residues 31-35 of SEQ ID NO: 407 for CDR-H1, residues 50-65 of SEQ ID NO: 407 for CDR-H2, and residues 95-102 of SEQ ID NO: 407 for CDR-H3, wherein the residues are numbered according to Kabat.

28. The antibody drug conjugate of claim 27 , wherein the anti-DLL3 antibody comprises a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 405 and a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 407.

29. The antibody drug conjugate of claim 28 , wherein the linker comprises a valine-alanine dipeptide.

30. The antibody drug conjugate of claim 29 comprising the structure:

wherein the asterisk indicates the point of attachment to the one or more PBDs, and wherein the wavy line indicates the point of attachment to the remaining portion of the linker.

31. The antibody drug conjugate of claim 26 , wherein the anti-DLL3 antibody is covalently linked to more than one PBD.

32. The antibody drug conjugate of claim 26 , wherein the ADC has a drug loading of 2.

33. The antibody drug conjugate of claim 26 , wherein 1 to 8 PBDs are covalently attached to the anti-DLL3 antibody.

34. A pharmaceutical composition comprising (a) the antibody drug conjugate of claim 26 , and (b) a pharmaceutically acceptable carrier.

35. The pharmaceutical composition of claim 34 comprising a drug to antibody ratio (DAR) of 1, 2, 3, 4, 5, 6, 7 or 8 each +/−0.4.

36. The pharmaceutical composition of claim 35 comprising a DAR of 2+/−0.4.

37. The pharmaceutical composition of claim 36 comprising less than 30% of non-predominant ADC species.

38. An antibody drug conjugate (ADC) comprising an anti-DLL3 antibody covalently linked through a linker to one or more pyrrolobenzodiazepines (PBDs),
wherein the anti-DLL3 antibody comprises a light chain variable region comprising a

Assignees

• Abbvie Stemcentrx Llc
• Medimmune Ltd

Inventors

• Torgov Michael
• Howard Philip Wilson

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P5/38

  of the suprarenal hormones · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P35/04

  specific for metastasis · CPC title