Methods for improving cardiac function by administering an antibody that activates APLNR

Patent metadata

Field	Value
Publication number	US-10189901-B2
Application number	US-201715480199-A
Country	US
Kind code	B2
Filing date	Apr 5, 2017
Priority date	Nov 20, 2013
Publication date	Jan 29, 2019
Grant date	Jan 29, 2019

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, which 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 for inducing vasodilation and/or angiogenesis in a subject, the method comprising administering a pharmaceutical composition to a subject in need thereof, wherein the pharmaceutical composition comprises an isolated antibody, antibody-fusion protein or antigen-binding fragment, wherein the antibody, antibody-fusion protein or antigen-binding fragment thereof comprises complementarity determining regions HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 having the amino acid sequences of SEQ ID NOs: 382-383-384-377-385-386, respectively, and wherein the antibody, antibody-fusion protein or antigen-binding fragment thereof activates apelin receptor (APLNR)-mediated inhibition of cAMP accumulation with at least 39% of maximum apelin dose response activation.

2. The method of claim 1 , wherein the isolated antibody, antibody-fusion protein or antigen-binding fragment activates APLNR-mediated inhibition of cAMP accumulation with at least 60% of maximum apelin dose response activation.

3. The method of claim 2 , wherein the antibody, antibody-fusion protein or antigen-binding fragment comprises a HCVR/LCVR amino acid sequence pair selected from the group consisting of: SEQ ID NOs: 287/295, 319/327, 335/343, 351/359, and 367/375.

4. The method of claim 1 , wherein the antibody, antibody-fusion protein or antigen-binding fragment comprises HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 domains, respectively, selected from the group consisting of: SEQ ID NOs: 289-291-293-297-299-301; 305-307-309-313-315-317; 321-323-325-329-331-333 ; 337-339-341-345-347-349; 353-355-357-361-363-365; and 369-371-373-377-379-381.

5. The method of claim 1 , wherein the antibody, antibody-fusion protein 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: 287, 303, 319, 335, 351, and 367; and (b) a light chain variable region (LCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 295, 311, 327, 343, 359, and 375.

6. The method of claim 1 , wherein the antibody, antibody-fusion protein or antigen-binding fragment comprises a HCVR/LCVR amino acid sequence pair selected from the group consisting of: SEQ ID NOs: 287/295, 303/311, 319/327, 335/343, 351/359, and 367/375.

7. The method of claim 1 , wherein the antibody, antibody-fusion protein or antigen-binding fragment thereof competes for binding to human apelin receptor (APLNR) with a reference antibody comprising an HCVR/LCVR sequence pair selected from the group consisting of SEQ ID NOs: 287/295, 303/311, 319/327, 335/343, 351/359, and 367/375.

8. The method of claim 1 , wherein the antibody,
antibody-fusion protein or antigen-binding fragment thereof binds to the same epitope on APLNR as a reference antibody comprising an HCVR/LCVR sequence pair selected from the group consisting of SEQ ID NOs: 287/295, 303/311, 319/327, 335/343, 351/359, and 367/375.

9. A method for treating an ischemic-reperfusion injury, the method comprising administering a pharmaceutical composition to a subject in need thereof, wherein the pharmaceutical composition comprises an isolated antibody, antibody-fusion protein or antigen-binding fragment, wherein the antibody, antibody-fusion protein or antigen-binding fragment thereof comprises complementarity determining regions HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 having the amino acid sequences of SEQ ID NOs: 382-383-384-377-385-386, respectively, and wherein the antibody, antibody-fusion protein or antigen-binding fragment thereof activates apelin receptor (APLNR)-mediated inhibition of cAMP accumulation with at least 39% of maximum apelin dose response activation.

10. A method for improving cardiac function, the method comprising administering a pharmaceutical composition to a subject in need thereof, wherein the pharmaceutical composition comprises an isolated antibody, antibody-fusion protein or antigen-binding fragment, wherein the antibody, antibody-fusion protein or antigen-binding fragment thereof comprises complementarity determining regions HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 having the amino acid sequences of SEQ ID NOs: 382-383-384-377-385-386, respectively, and wherein the antibody, antibody-fusion protein or antigen-binding fragment thereof activates apelin receptor (APLNR)-mediated inhibition of cAMP accumulation with at least 39% of maximum apelin dose response activation.

11. The method of claim 10 , wherein the subject suffers from a condition selected from congestive heart failure, myocardial infarction, or cardiomyopathy.

12. A method for inducing vasodilation and/or
angiogenesis in a subject, treating an ischemic-reperfusion injury in a subject, or improving cardiac function in a subject, the method comprising administering a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises an isolated antibody, antibody-fusion protein or antigen-binding fragment, wherein the antibody, antibody-fusion protein or antigen-binding fragment thereof comprises complementarity determining regions HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 having the amino acid sequences of SEQ ID NOs: 382-383-384-377-385-386, respectively, wherein X =N in SEQ ID NO:386, and wherein the antibody, antibody-fusion protein or antigen-binding fragment thereof activates apelin receptor (APLNR-mediated inhibition of cAMP accumulation with at least 60% of maximum apelin dose response activation.

13. The method of claim 12 , wherein the subject suffers from a condition selected from congestive heart failure, myocardial infarction, or cardiomyopathy.

Assignees

• Regeneron Pharma

Inventors

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

Classifications

• A61P9/10

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• A61P35/04

  specific for metastasis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P9/08

  Vasodilators for multiple indications · CPC title