Antibody modulators of APLNR
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.
1. 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 isolated antibody, antibody-fusion protein or antigen-binding fragment thereof of claim 1 that activates APLNR-mediated inhibition of cAMP accumulation with at least 60% of maximum apelin dose response activation.
3. The isolated antibody, antibody-fusion protein or antigen-binding fragment thereof 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.
4. The isolated antibody, antibody-fusion protein or antigen-binding fragment thereof 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.
5. The isolated antibody, antibody-fusion protein or antigen-binding fragment thereof 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.
6. The isolated antibody, antibody-fusion protein or antigen-binding fragment thereof 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.
7. The antibody, antibody-fusion protein or antigen-binding fragment 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 antibody, antibody-fusion protein or antigen-binding fragment 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 pharmaceutical composition comprising the antibody, antibody-fusion protein or antigen-binding fragment of claim 1 , and a pharmaceutically acceptable carrier or diluent.
10. 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.
11. A pharmaceutical composition comprising the antibody, antibody-fusion protein or antigen-binding fragment of claim 10 , and a pharmaceutically acceptable carrier or diluent.