Antibody-drug conjugates, their preparation and their therapeutic use

Patent metadata

Field	Value
Publication number	US-9951141-B2
Application number	US-201515314909-A
Country	US
Kind code	B2
Filing date	Jun 1, 2015
Priority date	Jun 2, 2014
Publication date	Apr 24, 2018
Grant date	Apr 24, 2018

Abstract

The present disclosure relates to conjugates comprising biologically active molecules linked to a multimeric antigen-binding compound or a multimeric immunoglobulin via a linker. The disclosure further provides reagents and methods of manufacturing the conjugates and the linkers. The disclosure also provides compositions comprising the conjugates, methods of modifying abnormal cell growth and methods of treatment using the conjugates or the compositions.

First claim

What is claimed is:

1. An antibody-drug conjugate comprising an antibody, or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof is conjugated to at least one moiety of Formula (A):

wherein:
Ab-S1 is a bond to a cysteine residue of the antibody or antigen binding fragment thereof;
Ab-S2 is a bond to a cysteine residue of the antibody or antigen binding fragment thereof;
X is —N(R A )— or —O—;
wherein R A is a hydrogen atom or alkyl;

R N and R M are each, independently, a hydrogen atom or alkyl;
A is absent or a spacer comprising a peptide,
wherein the peptide comprises 2-20 amino acids;

D is a biologically active molecule; and
b is an integer from 2 to 8.

2. The conjugate of claim 1 , wherein the antibody or antigen binding fragment thereof comprises at least one moiety of Formula (A) wherein Ab-S1 is a bond to a cysteine residue of a first heavy chain of the antibody or antigen binding fragment thereof and Ab-S2 is a bond to a cysteine residue of a second heavy chain of the antibody or antigen binding fragment thereof.

3. The conjugate of claim 1 , wherein the antibody or antigen binding fragment thereof comprises:
(i) two moieties of Formula (A) wherein each Ab-S1 is a bond to a cysteine residue of a first heavy chain of the antibody or antigen binding fragment thereof and each Ab-S2 is a bond to a cysteine residue atom of a second heavy chain of the antibody or antigen binding fragment thereof; and
(ii) two moieties of Formula (A) wherein each Ab-S1 is a bond to a cysteine residue of a light chain of the antibody or antigen binding fragment thereof and each Ab-S2AB is a bond to a cysteine residue of a heavy chain of the antibody of antigen binding fragment thereof.

4. The conjugate of claim 1 , wherein the conjugate comprises an anti-PRLR antibody.

5. The conjugate of claim 1 , wherein X is —NH—.

6. The conjugate of claim 1 , wherein X is —O—.

7. The conjugate of claim 1 , wherein X is —NH— or —O— and R N and R M are both hydrogen atoms.

8. The conjugate of claim 7 , wherein b is 4.

9. The conjugate of claim 1 wherein A is:

wherein

is the bond to D, and AA 1 and AA 2 are each, independently, an amino acid residue.

10. The conjugate of claim 9 , wherein A is:

wherein

is the bond to D.

11. The conjugate of claim 1 , wherein A is absent.

12. The conjugate of claim 1 , wherein D is an auristatin or a maytansinoid.

13. The conjugate of claim 1 , wherein D is MMAE, MMAD, or MMAF.

14. The conjugate of claim 1 , wherein D is a maytansinoid.

15. The conjugate of claim 1 , wherein D is DM1, DM4, or a derivative thereof.

16. The conjugate of claim 1 , wherein D is:

17. The conjugate of claim 1 , wherein D is:

18. The conjugate of claim 1 , wherein the moiety of Formula (A) is:

19. The conjugate of claim 1 , wherein the moiety of Formula (A) is:

20. The conjugate of claim 1 , wherein the moiety of Formula (A) is:

wherein D is a maytansinoid.

21. The conjugate of claim 1 , wherein the moiety of Formula (A) is:

wherein D is a maytansinoid.

22. The conjugate of claim 1 , wherein the moiety of Formula (A) is:

23. The conjugate of claim 1 , wherein the moiety of Formula (A) is:

24. The conjugate of claim 1 , wherein the moiety of Formula (A) is:

wherein D is an auristatin.

25. The conjugate of claim 1 , wherein the moiety of Formula (A) is:

wherein D is an auristatin.

26. The conjugate of claim 1 , wherein the moiety of Formula (A) is:

27. A compound of Formula (L1):

wherein:
R U is

wherein LG 1 and LG 2 , independently at each occurrence, are a leaving group;

X is —N(R A )— or —O—;
wherein R A is a hydrogen atom or alkyl;

R N and R M are each, independently, a hydrogen atom or alkyl;
A is absent or a spacer comprising a peptide,
wherein the peptide comprises 2-20 amino acids;

D is a biologically active molecule; and
b is an integer from 2 to 8.

28. A pharmaceutical composition comprising a therapeutically effective amount of a conjugate of claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents, or excipients.

29. A method of reducing, retarding or stopping an abnormal cell growth comprising contacting the abnormal cell with a conjugate of claim 1 , in an amount sufficient to retard, reduce or stop the abnormal cell growth, and wherein the abnormal cell growth is retarded, reduced or stopped.

30. A method of killing a cell, comprising contacting the cell with a conjugate of claim 1 , in an amount sufficient to kill the cell, and wherein the cell is killed.

31. A method of treating a medical disorder in an individual suffering from the medical disorder, comprising administering to the individual an effective amount of a composition comprising a conjugate of claim 1 .

32. The compound of claim 27 , wherein the leaving group is a halide.

33. The compound of claim 27 , wherein X is —NH—.

34. The compound of claim 27 , wherein X is —O—.

35. The compound of claim 27 , wherein R N and R M are both hydrogen atoms.

36. The compound of claim 27 , wherein b is an integer from 3-6.

37. The compound of claim 27 , wherein R N and R M are both hydrogen atoms and

Assignees

• Regeneron Pharma

Inventors

• Nittoli Thomas
• Kunz Arthur

Classifications

• A61K47/6801

  Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent · CPC title

• A61K2039/507

  Comprising a combination of two or more separate antibodies · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• A61P43/00

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