Anti-DPEP3 antibodies and methods of use

Patent metadata

Field	Value
Publication number	US-10189910-B2
Application number	US-201615181353-A
Country	US
Kind code	B2
Filing date	Jun 13, 2016
Priority date	Dec 12, 2013
Publication date	Jan 29, 2019
Grant date	Jan 29, 2019

Abstract

Provided herein are novel anti-DPEP3 antibodies and antibody drug conjugates (ADC), including derivatives thereof, and methods of using the same to treat proliferative disorders.

First claim

The invention claimed is:

1. An antibody drug conjugate comprising a monoclonal antibody conjugated, linked, or otherwise associated with a cytotoxic agent,
wherein the monoclonal antibody binds human DPEP3 and comprises three complementarity determining regions of a light chain variable region set forth as SEQ ID NO: 205 and three complementarity determining regions of a heavy chain variable region set forth as SEQ ID NO: 207.

2. The antibody drug conjugate of claim 1 , wherein mutating at least one of amino acids E217, R242, Q248, Q372, K375, and E379 of SEQ ID NO: 3 results in loss of binding of the antibody to DPEP3.

3. The antibody drug conjugate of claim 1 , wherein the monoclonal antibody binds to an epitope on human DPEP3 that comprises residues E217, R242, Q248, Q372, K375, and E379.

4. The antibody drug conjugate of claim 1 , wherein the monoclonal antibody is a chimeric, CDR grafted, or humanized antibody.

5. The antibody drug conjugate of claim 1 , comprising the formula Ab-[L-D]n, wherein:
a) Ab comprises the antibody;
b) L comprises an optional linker;
c) D comprises a drug, which is the cytotoxic agent; and
d) n is an integer from about 1 to about 20.

6. The antibody drug conjugate of claim 1 , wherein the cytotoxic agent is a pyrrolobenzodiazepine (PBD).

7. A pharmaceutical composition comprising (i) the antibody drug conjugate of claim 1 and (ii) a pharmaceutically acceptable carrier.

8. The antibody drug conjugate of claim 1 , wherein the antibody comprises residues 24-34 of SEQ ID NO: 205 for CDRL1, residues 50-56 of SEQ ID NO: 205 for CDRL2, residues 89-97 of SEQ ID NO: 205 for CDRL3, residues 31-35 of SEQ ID NO: 207 for CDRH1, residues 50-65 of SEQ ID NO: 207 for CDRH2 and residues 95-102 of SEQ ID NO: 207 for CDRH3, wherein the CDR residues are numbered according to Kabat.

9. The antibody drug conjugate of claim 1 , wherein the antibody comprises residues 24-34 of SEQ ID NO: 205 for CDRL1, residues 50-56 of SEQ ID NO: 205 for CDRL2, residues 89-97 of SEQ ID NO: 205 for CDRL3, residues 26-32 of SEQ ID NO: 207 for CDRH1, residues 52-56 of SEQ ID NO: 207 for CDRH2 and residues 95-102 of SEQ ID NO: 207 for CDRH3, wherein the CDR residues are numbered according to Chothia.

10. The antibody drug conjugate of claim 1 , wherein the antibody comprises residues 30-36 of SEQ ID NO: 205 for CDRL1, residues 46-55 of SEQ ID NO: 205 for CDRL2, residues 89-96 of SEQ ID NO: 205 for CDRL3, residues 30-35 of SEQ ID NO: 207 for CDRH1, residues 47-58 of SEQ ID NO: 207 for CDRH2 and residues 93-101 of SEQ ID NO: 207 for CDRH3, wherein the CDR residues are numbered according to MacCallum.

11. The antibody drug conjugate of claim 1 , wherein the antibody comprises residues 24-34 of SEQ ID NO: 205 for CDRL1, residues 50-56 of SEQ ID NO: 205 for CDRL2, residues 89-97 of SEQ ID NO: 205 for CDRL3, residues 26-35 of SEQ ID NO: 207 for CDRH1, residues 50-58 of SEQ ID NO: 207 for CDRH2 and residues 95-102 of SEQ ID NO: 207 for CDRH3, wherein the CDR residues are numbered according to AbM.

12. The antibody drug conjugate of claim 1 , wherein the antibody comprises a light chain variable region set forth as SEQ ID NO: 205 and a heavy chain variable region set forth as SEQ ID NO: 207.

13. The antibody drug conjugate of claim 1 , wherein the antibody comprises two light chains and two heavy chains, wherein each of the two light chains comprises a sequence set forth as SEQ ID NO: 224 and each of the two heavy chains comprises a sequence set forth as SEQ ID NO: 225.

14. The antibody drug conjugate of claim 1 , wherein the antibody comprises two light chains, two heavy chains, and two unpaired cysteine residues.

15. The antibody drug conjugate of claim 14 , wherein each of the two light chains comprises an unpaired cysteine residue.

16. The antibody drug conjugate of claim 15 , wherein the two light chains each comprise an unpaired cysteine residue at position C214.

17. The antibody drug conjugate of claim 14 , wherein each of the two heavy chains comprises an unpaired cysteine residue.

18. The antibody drug conjugate of claim 17 , wherein each of the two heavy chains comprise IgG1 comprising an unpaired cysteine residue at position C220.

19. The antibody drug conjugate of claim 14 , wherein the antibody comprises an IgG1 monoclonal antibody comprising (i) a cysteine residue at heavy chain position 220 and a deletion of a cysteine residue at light chain position 214; (ii) a cysteine residue at heavy chain position 220 and a substitution of a cysteine residue at light chain position 214; (iii) a cysteine residue at light chain position 214 and a deletion of a cysteine residue at heavy chain position 220; or (iv) a cysteine residue at light chain position 214 and a substitution of a cysteine residue at heavy chain position 220; and
wherein the antibody comprises native cysteine residues at heavy chain positions 226 and 229.

20. The antibody drug conjugate of claim 14 , wherein each of the two light chains comprises a sequence set forth as SEQ ID NO: 224 and each of the two heavy chains comprises a sequence set forth as SEQ ID NO: 226.

21. The antibody drug conjugate of claim 1 , wherein the antibody is conjugated to the cytotoxic agent.

22. The antibody drug conjugate of claim 1 , wherein the cytotoxic agent is a pyrrolobenzodiazepine having the structure:

23. The antibody drug conjugate of claim 1 , wherein the antibody comprises a light chain variable region set forth as SEQ ID NO: 205 and a heavy chain variable region set forth as SEQ ID NO: 207 and wherein the cytotoxic agent is a pyrrolobenzodiazepine having the structure:

24. The antibody drug conjugate of claim 1 , wherein the antibody comprises two light chains and two heavy chains, wherein each of the two light chains comprises a sequence set forth as SEQ ID NO: 224 and each of the two heavy chains comprises a sequence set forth as SEQ ID NO: 226, and wherein the cytotoxic agent is a pyrrolobenzodiazepine having the structure:

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

26. The antibody drug conjugate of claim 25 , comprising a linker.

27. The antibody drug conjugate of claim 26 , wherein the linker is a cleavable linker.

28. The antibody drug conjugate of claim 27 , wherein the linker comprises a maleimide linker.

29. The pharmaceutical composition of claim 7 , comprising a drug to antibody ratio (DAR) of 1, 2, 3, 4, 5, 6, 7 or 8 each ±0.4.

30. The pharmaceutical composition of claim 7 , comprising a drug to antibody ratio (DAR) of 2±0.4.

31. The pharmaceutical composition of claim 30 , comprising less than 30% of non-predominant antibody drug conjugate species.

32. The pharmaceutical formulation of claim 7 , wherein the antibody drug conjugate further comprises a linker and wherein:
(a) the antibody comprises a light chain variable region set forth as SEQ ID NO: 205 and a heavy chain variable region set forth as SEQ ID NO: 207; and
(b) the cytotoxic agent is a pyrrolo

Assignees

• Abbvie Stemcentrx Llc

Inventors

• Saunders Laura
• Rokkam Deepti
• Liu David
• Boontanrart Mandy

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07K2317/33

  Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity · CPC title

• A61K47/6851

  the antibody targeting a determinant of a tumour cell · CPC title

• C07K2317/56

  variable (Fv) region, i.e. VH and/or VL · CPC title

• C07K16/40 Primary

  against enzymes · CPC title