Anti-neuropilin antigen-binding proteins and methods of use thereof
Provided herein are antibodies, or antigen binding fragments thereof, that selectively bind to NRP-1 and its isoforms and homologs, and compositions comprising the antibodies, or antigen binding fragments thereof. Also provided are methods of using the antibodies, or antigen binding fragments thereof, such as therapeutic and diagnostic methods.
1. An isolated antibody, or antigen binding fragment thereof, that specifically binds human NRP-1 (hNRP-1; SEQ ID NO:130), wherein the antibody, or antigen binding fragment thereof, comprises the following six CDR sequences:
(a) a CDR-H3 having the sequence set forth in SEQ ID NO:47;
(b) a CDR-H2 having the sequence X 1 ISGSGGX 2 TYYADSVX 3 G, wherein X 1 is I or A, X 2 is S or A, and X 3 is K or E, as set forth in SEQ ID NO:136;
(c) a CDR-H1 having the sequence FTFX 1 SX 2 AMV, wherein X 1 is A, K, or S and X 2 is Y or V, as set forth in SEQ ID NO:137;
(d) a CDR-L3 having the sequence set forth in SEQ ID NO:81;
(e) a CDR-L2 having the sequence set forth in SEQ ID NO:71; and
(f) a CDR-L1 having the sequence set forth in SEQ ID NO:63.
2. The antibody, or antigen binding fragment thereof, of claim 1 , wherein the antibody, or antigen binding fragment thereof, comprises:
(a) a CDR-H3 of SEQ ID NO:47, a CDR-H2 of SEQ ID NO:27, a CDR-H1 of SEQ ID NO:12, a CDR-L3 of SEQ ID NO:81, a CDR-L2 of SEQ ID NO:71, and a CDR-L1 of SEQ ID NO:63;
(b) a CDR-H3 of SEQ ID NO:47, a CDR-H2 of SEQ ID NO:28, a CDR-H1 of SEQ ID NO:13, a CDR-L3 of SEQ ID NO:81, a CDR-L2 of SEQ ID NO:71, and a CDR-L1 of SEQ ID NO:63;
(c) a CDR-H3 of SEQ ID NO:47, a CDR-H2 of SEQ ID NO:29, a CDR-H1 of SEQ ID NO:14, a CDR-L3 of SEQ ID NO:81, a CDR-L2 of SEQ ID NO:71, and a CDR-L1 of SEQ ID NO:63; or
(d) a CDR-H3 of SEQ ID NO:47, a CDR-H2 of SEQ ID NO:30, a CDR-H1 of SEQ ID NO:14, a CDR-L3 of SEQ ID NO:81, a CDR-L2 of SEQ ID NO:71, and a CDR-L1 of SEQ ID NO:63.
3. The antibody, or antigen binding fragment thereof, of claim 2 , wherein:
(a) the antibody, or antigen binding fragment thereof, of claim 2 (a) comprises a V H sequence of SEQ ID NO:92 and a V L sequence of SEQ ID NO:104;
(b) the antibody, or antigen binding fragment thereof, of claim 2 (b) comprises a V H sequence of SEQ ID NO:93 and a V L sequence of SEQ ID NO:104;
(c) the antibody, or antigen binding fragment thereof, of claim 2 (c) comprises a V H sequence of SEQ ID NO:94 and a V L sequence of SEQ ID NO:104;
(d) the antibody, or antigen binding fragment thereof, of claim 2 (d) comprises a V H sequence of SEQ ID NO:95 and a V L sequence of SEQ ID NO:104; or
(e) the antibody, or antigen binding fragment thereof, of claim 2 (d) comprises a V H sequence of SEQ ID NO:96 and a V L sequence of SEQ ID NO:104.
4. The antibody, or antigen binding fragment thereof, of claim 3 , wherein:
(a) the antibody, or antigen binding fragment thereof, of claim 2 (a) comprises a heavy chain of SEQ ID NO:114 and a light chain of SEQ ID NO:126;
(b) the antibody, or antigen binding fragment thereof, of claim 2 (b) comprises a heavy chain of SEQ ID NO:115 and a light chain of SEQ ID NO:126;
(c) the antibody, or antigen binding fragment thereof, of claim 2 (c) comprises a heavy chain of SEQ ID NO:116 and a light chain of SEQ ID NO:126;
(d) the antibody, or antigen binding fragment thereof, of claim 2 (d) comprises a heavy chain of SEQ ID NO:117 and a light chain of SEQ ID NO:126; or
(e) the antibody, or antigen binding fragment thereof, of claim 2 (d) comprises a heavy chain of SEQ ID NO:118 and a light chain of SEQ ID NO:126.
5. The antibody, or antigen binding fragment thereof, of claim 1 , wherein the antibody, or antigen binding fragment thereof, specifically antagonizes hNRP-1 binding to a neuropilin-1 ligand.
6. The antibody, or antigen binding fragment thereof, of claim 1 , wherein the antibody, or antigen binding fragment thereof, specifically binds one or more residues on hNRP-1 (SEQ ID NO:130) selected from the group consisting of Y297, T316, D320, E348, T349, K350, K351, K352, Y353, Y354, E412, T413, G414, and I415.
7. The antibody, or antigen binding fragment thereof, of claim 1 , wherein the antibody, or antigen binding fragment thereof, specifically binds to NRP-1 from humans (SEQ ID NO:130), mice, and cynomolgus monkeys.
8. The antibody, or antigen binding fragment thereof, of claim 1 , wherein the antibody, or antigen binding fragment thereof, binds to a different epitope on hNRP-1 than the epitope on hNRP-1 to which SEC10 binds, wherein the SEC10 comprises a heavy chain of SEQ ID NO: 141 and a light chain of SEQ ID NO: 142.
9. The antibody, or antigen binding fragment thereof, of claim 1 , wherein the antibody, or antigen binding fragment thereof, specifically binds to the b1 domain of hNRP-1.
10. The antibody, or antigen binding fragment thereof, of claim 1 , wherein the antibody, or antigen binding fragment thereof, antagonizes the interaction between a hNRP-1 polypeptide and one or both of a vascular endothelial cell growth factor (VEGF) polypeptide and a semaphorin (SEMA) polypeptide.
11. A pharmaceutical composition comprising an antibody, or antigen binding fragment thereof, of claim 1 and a pharmaceutically acceptable excipient.