Anti-PRLR antibodies and methods for killing PRLR-expressing cells

Patent metadata

Field	Value
Publication number	US-9302015-B2
Application number	US-201414464297-A
Country	US
Kind code	B2
Filing date	Aug 20, 2014
Priority date	Aug 21, 2013
Publication date	Apr 5, 2016
Grant date	Apr 5, 2016

Abstract

The present invention provides antibodies that bind to prolactin receptor (PRLR) and methods of using the same. According to certain embodiments, the antibodies of the invention bind human PRLR with high affinity. In certain embodiments, the invention includes antibodies that bind PRLR and block prolactin-mediated cell signaling. In other embodiments, the invention includes antibodies that bind PRLR but do not block prolactin-mediated cell signaling. The antibodies of the invention may be fully human antibodies. The invention includes anti-PRLR antibodies conjugated to a cytotoxic agent, radionuclide, or other moiety detrimental to cell growth or proliferation. The antibodies of the invention are useful for the treatment of various cancers as well as other PRLR-related disorders. The present invention also includes antibody drug conjugates comprising an antibody or antigen-binding fragment thereof that specifically binds a class I cytokine receptor, wherein the antibody or antigen-binding fragment thereof is conjugated to a cytotoxic agent.

First claim

What is claimed is:

1. An isolated antibody or antigen-binding fragment that binds to cell surface-expressed human prolactin receptor (PRLR) and blocks prolactin-mediated signaling in cells expressing human PRLR, wherein the antibody or antigen-binding fragment thereof blocks prolactin-mediated signaling in cells expressing human PRLR with an IC 50 of less than about 1.3 nM.

2. The isolated antibody or antigen-binding fragment of claim 1 that blocks prolactin-mediated signaling in cells expressing human PRLR with an IC 50 of less than about 1.2 nM.

3. The isolated antibody or antigen-binding fragment of claim 1 that blocks prolactin-mediated signaling in cells expressing human PRLR with an IC 50 of less than about 1.0 nM.

4. The isolated antibody or antigen-binding fragment of claim 1 that blocks prolactin-mediated signaling in cells expressing human PRLR with an IC 50 of less than about 900 pM.

5. The isolated antibody or antigen-binding fragment of claim 1 that blocks prolactin-mediated signaling in cells expressing human PRLR with an IC 50 of less than about 800 pM.

6. The isolated antibody or antigen-binding fragment of claim 1 that blocks prolactin-mediated signaling in cells expressing human PRLR with an IC 50 of less than about 600 pM.

7. The isolated antibody or antigen-binding fragment of claim 1 that blocks prolactin-mediated signaling in cells expressing human PRLR with an IC 50 of less than about 400 pM.

8. The isolated antibody or antigen-binding fragment of claim 1 that blocks prolactin-mediated signaling in cells expressing human PRLR with an IC 50 of less than about 200 pM.

9. The isolated antibody or antigen-binding fragment of claim 1 that blocks prolactin-mediated signaling in cells expressing human PRLR with an IC 50 of less than about 100 pM.

10. The isolated antibody or antigen-binding fragment of claim 1 that blocks prolactin-mediated signaling in cells expressing human PRLR with an IC 50 of less than about 80 pM.

11. The isolated antibody or antigen-binding fragment of claim 1 that blocks prolactin-mediated signaling in cells expressing human PRLR with an IC 50 of less than about 60 pM.

12. The isolated antibody or antigen-binding fragment of claim 1 that blocks prolactin-mediated signaling in cells expressing human PRLR with an IC 50 of less than about 40 pM.

13. The antibody or antigen-binding fragment of claim 1 that competes for binding to PRLR with a reference antibody comprising an HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs: 18/26; 66/74; 274/282; 290/298; and 370/378.

14. An antibody-drug conjugate (ADC) comprising an antibody or antigen-binding fragment thereof that specifically binds cell-surface expressed human prolactin receptor (PRLR), wherein the antibody or fragment is conjugated to a cytotoxic agent, wherein the ADC inhibits the growth of cells expressing PRLR, and wherein the antibody or antigen-binding fragment thereof blocks prolactin-mediated signaling in cells expressing human PRLR with an IC 50 of less than about 1.3 nM.

15. The ADC of claim 14 , wherein the cytotoxic agent is a maytansinoid.

16. The ADC of claim 15 , wherein the maytansinoid is DM1, DM4, or a derivative thereof.

17. The ADC of claim 15 , wherein the maytansinoid is connected to the antibody via a cleavable linker.

18. The ADC of claim 15 , wherein the maytansinoid is connected to the antibody via a non-cleavable linker.

19. The ADC of claim 14 , wherein the ADC kills cells that express PRLR at an expression level of less than 30-fold above background.

20. The ADC of claim 19 , wherein the ADC kills cells that express PRLR at an expression level of less than 20-fold above background.

21. The ADC of claim 20 , wherein the ADC kills cells that express PRLR at an expression level greater than 12-fold above background but less than 30-fold above background.

22. The ADC of claim 14 , wherein the antibody or antigen-binding fragment thereof competes for binding to PRLR with a reference antibody comprising an HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs: 18/26; 66/74; 274/282; 290/298; and 370/378.

23. The ADC of claim 14 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO:292; an HCDR2 comprising SEQ ID NO:294; an HCDR3 comprising SEQ ID NO:296; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO:300; an LCDR2 comprising SEQ ID NO:302; and an LCDR3 comprising SEQ ID NO:304.

24. The ADC of claim 23 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising SEQ ID NO:290 and a light chain variable region (LCVR) comprising SEQ ID NO:298.

25. The ADC of claim 14 that blocks prolactin-mediated signaling in cells expressing human PRLR with an IC 50 of less than about 1.2 nM.

26. The ADC of claim 14 that blocks prolactin-mediated signaling in cells expressing human PRLR with an IC 50 of less than about 1.0 nM.

27. The ADC of claim 14 that blocks prolactin-mediated signaling in cells expressing human PRLR with an IC 50 of less than about 900 pM.

28. The ADC of claim 14 that blocks prolactin-mediated signaling in cells expressing human PRLR with an IC 50 of less than about 800 pM.

29. The ADC of claim 14 that blocks prolactin-mediated signaling in cells expressing human PRLR with an IC 50 of less than about 600 pM.

30. The ADC of claim 14 that blocks prolactin-mediated signaling in cells expressing human PRLR with an IC 50 of less than about 400 pM.

31. The ADC of claim 14 that blocks prolactin-mediated signaling in cells expressing human PRLR with an IC 50 of less than about 200 pM.

32. The ADC of claim 14 that blocks prolactin-mediated signaling in cells expressing human PRLR with an IC 50 of less than about 100 pM.

33. The ADC of claim 14 that blocks prolactin-mediated signaling in cells expressing human PRLR with an IC 50 of less than about 80 pM.

34. The ADC of claim 14 that blocks prolactin-mediated signaling in cells expressing human PRLR with an IC 50 of less than about 60 pM.

35. The ADC of claim 14 that blocks prolactin-mediated signaling in cells expressing human PRLR with an IC 50 of less than about 40 pM.

36. The ADC of claim 16 , wherein the maytansinoid is connected to the antibody via an N-succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) linker.

37. The ADC of claim 36 , wherein the maytansinoid is DM1.

38. The ADC of claim 37 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO:292; an HCDR2 comprising SEQ ID NO:294; an HCDR3 comprising SEQ ID NO:296; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO:300; an LCDR2 comprising SEQ ID NO:302; and an LCDR3 comprising SEQ ID NO:304.

39. The ADC of claim 38 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising SEQ ID NO:290 and a light chain variable region (LCVR) comprising SEQ ID NO:298.

Assignees

• Regeneron Pharma

Inventors

• Papadopoulos Nicholas J
• Thurston Gavin
• Kirshner Jessica R
• Kelly Marcus P
• Nittoli Thomas
• Delfino Frank J

Classifications

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• C07K2317/56

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

• A61K47/6849

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title