Anti-TIE2 antibodies and uses thereof
The present invention provides antibodies that bind to Tie2 and methods of using same. According to certain embodiments of the invention, the antibodies are fully human antibodies that bind to human Tie2 and block the interaction between Tie2 and one or more Tie2 ligands such as angiopoietin 1 (Ang1), angiopoietin 2 (Ang2), angiopoietin 3 (Ang3) and/or angiopoietin 4 (Ang4). The antibodies of the invention are useful, inter alia, for the treatment of diseases and disorders associated with one or more Tie2 biological activities including angiogenesis. In certain embodiments, pairs of activating Tie-2 antibodies showed an additive effect on the treatment of influenza infection when combined with anti-influenza HA. In other embodiments, prophylactic administration pairs of activating Tie2 antibodies delayed death and improved survival in a lethal model of E. coli intoxication (sepsis) over isotype/untreated controls.
1. An isolated antibody or antigen-binding fragment thereof that binds human Tie2 receptor, wherein the antibody or antigen-binding fragment thereof comprises: (a) the complementarity determining regions (CDRs) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 20, SEQ ID NO: 36, or SEQ ID NO: 52 and (b) the CDRs of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 28, SEQ ID NO: 44, or SEQ ID NO: 60.
2. The isolated antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment comprises the heavy and light chain CDRs of an HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs: 20/28, 36/44, and 52/60.
3. The isolated antibody or antigen-binding fragment thereof of claim 2 , wherein the antibody or antigen-binding fragment thereof activates Tie2 signaling.
4. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of claim 2 , and a pharmaceutically acceptable carrier or diluent.
5. The isolated antibody or antigen-binding fragment of claim 2 , wherein the antibody or antigen-binding fragment thereof comprises:
(a) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 22;
(b) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 24;
(c) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 26;
(d) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30;
(e) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 32; and
(f) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 34.
6. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of claim 5 , and a pharmaceutically acceptable carrier or diluent.
7. The isolated antibody or antigen-binding fragment of claim 2 , wherein the antibody or antigen-binding fragment thereof comprises:
(a) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 38;
(b) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 40;
(c) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 42;
(d) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 46;
(e) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 48; and
(f) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 50.
8. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of claim 7 , and a pharmaceutically acceptable carrier or diluent.
9. The isolated antibody or antigen-binding fragment of claim 2 , wherein the antibody or antigen-binding fragment thereof comprises:
(a) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 54;
(b) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 56;
(c) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 58;
(d) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 62;
(e) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 64; and
(f) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 66.
10. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of claim 9 , and a pharmaceutically acceptable carrier or diluent.
11. The isolated antibody or antigen-binding fragment thereof of claim 2 , wherein the antibody or antigen-binding fragment thereof comprises an HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs: 20/28, 36/44, and 52/60.
12. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of claim 11 , and a pharmaceutically acceptable carrier or diluent.
13. The isolated antibody or antigen-binding fragment of claim 11 , which is an antibody.
14. The isolated antibody of claim 13 , wherein the isolated antibody comprises an IgG4 heavy chain constant region.
15. The isolated antibody of claim 13 , wherein the isolated antibody comprises an IgG1 heavy chain constant region.
16. The antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment thereof competes for binding to Tie2 with a reference antibody comprising an HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs: 20/28, 36/44, and 52/60.
17. The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof binds to the same epitope on Tie2 as a reference antibody comprising an HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs: 20/28, 36/44, and 52/60.
18. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of claim 1 , and a pharmaceutically acceptable carrier or diluent.
19. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises an HCVR amino acid sequence selected from the group consisting of SEQ ID NOs: 20, 36, and 52.
20. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises an LCVR amino acid sequence selected from the group consisting of SEQ ID NOs: 28, 44, and 60.