Method for treating pathological angiogenesis by administering an antibody that inhibits APLNR

Patent metadata

Field	Value
Publication number	US-10626173-B2
Application number	US-201816175357-A
Country	US
Kind code	B2
Filing date	Oct 30, 2018
Priority date	Nov 20, 2013
Publication date	Apr 21, 2020
Grant date	Apr 21, 2020

Abstract

The present invention provides apelin receptor (APLNR) modulators that bind to APLNR and methods of using the same. The invention includes APLNR modulators such as antibodies, or antigen-binding fragments thereof, that inhibit or attenuate APLNR-mediated signaling. The invention includes APLNR modulators such as antibodies, or antibody fusion proteins thereof, that activate APLNR-mediated signaling. According to certain embodiments of the invention, the antibodies or antigen-binding fragments or antibody fusion proteins are fully human antibodies that bind to human APLNR with high affinity. The APLNR modulators of the invention are useful for the treatment of diseases and disorders associated with APLNR signaling and/or APLNR cellular expression, such as cardiovascular diseases, angiogenesis diseases, metabolic diseases and fibrotic diseases.

First claim

What is claimed is:

1. A method of treating cancer or metastatic disease, comprising administering, to a patient in need thereof, a therapeutically effective amount of an isolated antibody or antigen-binding fragment thereof that binds to apelin receptor (APLNR) and blocks the interaction of APLNR and apelin, wherein the antibody or antigen-binding fragment comprises: (a) the complementarity determining regions (CDRs) of a heavy chain variable region (HCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 82, 98, and 130; and (b) the CDRs of a light chain variable region (LCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106, and 138.

2. The method of claim 1 , wherein the antibody or antigen-binding fragment comprises HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 domains, respectively, selected from the group consisting of: SEQ ID NOs: 4-6-8-12-14-16; 20-22-24-28-30-32; 36-38-40-44-46-48; 52-54-56-60-62-64; 68-70-72-76-78-80; 84-86-88-92-94-96; 100-102-104-108-110-112; and 132-134-136-140-142-144.

3. The method of claim 1 , wherein the antibody or antigen-binding fragment comprises: (a) a heavy chain variable region (HCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 82, 98, and 130; and (b) a light chain variable region (LCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106, and 138.

4. The method of claim 3 , wherein the antibody or antigen-binding fragment comprises a HCVR/LCVR amino acid sequence pair selected from the group consisting of: SEQ ID NOs: 2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, and 130/138.

5. The method of claim 4 , wherein the antibody or antigen-binding fragment comprises the HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 98/106.

6. The method of claim 4 , wherein the antibody or antigen-binding fragment comprises the HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 2/10.

7. The method of claim 4 , wherein the antibody or antigen-binding fragment comprises the HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 18/26.

8. The method of claim 4 , wherein the antibody or antigen-binding fragment comprises the HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 130/138.

9. The method of claim 1 , wherein the antibody or antigen-binding fragment comprises the CDRs of a HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 98/106.

10. The method of claim 1 , wherein the antibody or antigen-binding fragment comprises the CDRs of a HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 2/10.

11. The method of claim 1 , wherein the antibody or antigen-binding fragment comprises the CDRs of a HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 18/26.

12. The method of claim 1 , wherein the antibody or antigen-binding fragment comprises the CDRs of a HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 130/138.

13. The method of claim 1 , wherein the antibody or antigen-binding fragment comprises the CDRs of a HCVR/LCVR amino acid sequence pair selected from the group consisting of: SEQ ID NOs: 34/42, 50/58, 66/74, and 82/90.

14. A method of treating retinopathy, comprising administering, to a patient in need thereof, a therapeutically effective amount of an isolated antibody or antigen-binding fragment thereof that binds to apelin receptor (APLNR) and blocks the interaction of APLNR and apelin, wherein the antibody or antigen-binding fragment comprises: (a) the complementarity determining regions (CDRs) of a heavy chain variable region (HCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 82, 98, and 130; and (b) the CDRs of a light chain variable region (LCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106, and 138.

15. The method of claim 14 , wherein the antibody or antigen-binding fragment comprises a HCVR/LCVR amino acid sequence pair selected from the group consisting of: SEQ ID NOs: 2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, and 130/138.

16. The method of claim 14 , wherein the antibody or antigen-binding fragment comprises the CDRs of a HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 98/106.

17. The method of claim 14 , wherein the antibody or antigen-binding fragment comprises the HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 98/106.

18. A method of treating pathological angiogenesis, comprising administering, to a patient in need thereof, a therapeutically effective amount of an isolated antibody or antigen-binding fragment thereof that binds to apelin receptor (APLNR) and blocks the interaction of APLNR and apelin, wherein the antibody or antigen-binding fragment comprises: (a) the complementarity determining regions (CDRs) of a heavy chain variable region (HCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 82, 98, and 130; and (b) the CDRs of a light chain variable region (LCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106, and 138.

19. The method of claim 18 , wherein the antibody or antigen-binding fragment comprises HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 domains, respectively, selected from the group consisting of: SEQ ID NOs: 4-6-8-12-14-16; 20-22-24-28-30-32; 36-38-40-44-46-48; 52-54-56-60-62-64; 68-70-72-76-78-80; 84-86-88-92-94-96; 100-102-104-108-110-112; and 132-134-136-140-142-144.

20. The method of claim 18 , wherein the antibody or antigen-binding fragment comprises a HCVR/LCVR amino acid sequence pair selected from the group consisting of: SEQ ID NOs: 2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, and 130/138.

Assignees

• Regeneron Pharma

Inventors

• Stevis Panayiotis
• Gromada Jesper
• Murphy Andrew J
• Ray Yonaton
• Kim Jee H
• Lobov Ivan B

Classifications

• C07K16/2869 Primary

  against hormone receptors (for antibodies against neuromediator receptors C07K16/286) · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• C07K2317/92

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

• C07K2317/565

  Complementarity determining region [CDR] · CPC title

• C07K2317/74

  Inducing cell proliferation · CPC title