Anti-neuropilin antigen-binding proteins and methods of use thereof

Abstract

Provided herein are antigen-binding proteins (ABPs) that selectively bind to NRP-1 and its isoforms and homologs, and compositions comprising the ABPs. Also provided are methods of using the ABPs, such as therapeutic and diagnostic methods.

1 - 21 . (canceled) 
     
     
         22 . A method of preventing or treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of an antigen binding protein (ABP) that specifically binds human NRP-1 (hNRP-1; SEQ ID NO:130), wherein the ABP 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,   thereby preventing or treating cancer in the subject.   
     
     
         23 . The method of  claim 22 , wherein the ABP 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.   
     
     
         24 . The method of  claim 23 , wherein:
 (a) the ABP of claim  2 (a) comprises a VH sequence of SEQ ID NO:92 and a VL sequence of SEQ ID NO:104;   (b) the ABP of claim  2 (b) comprises a VH sequence of SEQ ID NO:93 and a VL sequence of SEQ ID NO:104;   (c) the ABP of claim  2 (c) comprises a VH sequence of SEQ ID NO:94 and a VL sequence of SEQ ID NO:104;   (d) the ABP of claim  2 (d) comprises a VH sequence of SEQ ID NO:95 and a VL sequence of SEQ ID NO:104; or   (e) the ABP of claim  2 (d) comprises a VH sequence of SEQ ID NO:96 and a VL sequence of SEQ ID NO:104.   
     
     
         25 . The method of  claim 24 , wherein:
 (a) the ABP of claim  2  (a) comprises a heavy chain of SEQ ID NO:114 and a light chain of SEQ ID NO:126;   (b) the ABP of claim  2 (b) comprises a heavy chain of SEQ ID NO:115 and a light chain of SEQ ID NO:126;   (c) the ABP of claim  2 (c) comprises a heavy chain of SEQ ID NO:116 and a light chain of SEQ ID NO:126;   (d) the ABP 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 ABP of claim  2 (d) comprises a heavy chain of SEQ ID NO:118 and a light chain of SEQ ID NO:126.   
     
     
         26 . The method of  claim 22 , wherein the ABP specifically antagonizes hNRP-1 binding to a neuropilin-1 ligand. 
     
     
         27 . The method of  claim 22 , wherein the ABP 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 1415. 
     
     
         28 . The method of  claim 22 , wherein the ABP specifically binds to NRP-1 from humans, mice, and cynomolgus monkeys. 
     
     
         29 . The method of  claim 22 , wherein the ABP 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. 
     
     
         30 . The method of  claim 22 , wherein the ABP specifically binds to the b1 domain of hNRP-1. 
     
     
         31 . The method of  claim 22 , wherein the ABP 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. 
     
     
         32 . The method of  claim 22 , wherein the method induces or enhances an immune response to a cancer-associated antigen. 
     
     
         33 . The method of  claim 22 , wherein the ABP is capable of decreasing Treg survival in the subject, binding to an extracellular domain of the NRP, or a combination thereof. 
     
     
         34 . The method of  claim 22 , further comprising administering one or more additional therapeutic agents to the subject. 
     
     
         35 . The method of  claim 34 , wherein the additional therapeutic agent is selected from the group consisting of radiation, a cytotoxic agent, a chemotherapeutic agent, a cytostatic agent, an anti-hormonal agent, a VEGF inhibitor, an immunostimulatory agent, an anti-angiogenic agent, and combinations thereof. 
     
     
         36 . The method of  claim 35 , wherein the additional therapeutic agent is an immunostimulatory agent. 
     
     
         37 . The method of  claim 36 , wherein the immunostimulatory agent comprises: (i) an agent that blocks signaling of an inhibitory receptor expressed by an immune cell or a ligand thereof; (ii) an agonist to a stimulatory receptor expressed by an immune cell; (iii) a cytokine; or (iv) a vaccine to a cancer-associated antigen. 
     
     
         38 . The method of  claim 36 , wherein the immunostimulatory agent is an anti-PD-1 antibody. 
     
     
         39 . The method of  claim 38 , wherein the anti-PD-1 antibody is pembrolizumab, nivolumab, or a combination thereof. 
     
     
         40 . A method of modulating an immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of an antigen binding protein (ABP) that specifically binds human NRP-1 (hNRP-1; SEQ ID NO:130), wherein the ABP 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,   thereby modulating an immune response in the subject.   
     
     
         41 . A method of increasing T effector cell (Teff) function in a subject in need thereof, the method comprising administering to the subject an effective amount of
 an antigen binding protein (ABP) that specifically binds human NRP-1 (hNRP-1; SEQ ID NO:130), wherein the ABP 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,   thereby increasing T effector cell (Teff) function in the subject.