Anti-notch2 nrr antibodies

Abstract

The invention provides anti-Notch antibodies, and in particular, antibodies that bind Notch2 NRR, and methods of using the same.

1 . A monoclonal antibody that binds to Notch2 negative regulatory region (NRR) and inhibits Notch2 activity, wherein the antibody binds both human and mouse Notch2 NRR with a Kd of ≦10 nM, and wherein the antibody comprises a heavy chain variable domain having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:20 and a light chain variable domain having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:22. 
     
     
         2 - 4 . (canceled) 
     
     
         5 . The antibody of  claim 1 , wherein the antibody comprises:
 (a) a heavy chain hypervariable region (HVR-H) comprising the amino acid sequence of SEQ ID NO:3;   (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO:4;   (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:5;   (d) a light chain hypervariable region (HVR-L) comprising the amino acid sequence of SEQ ID NO:10;   (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO:14; and   (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:19.   
     
     
         6 . (canceled) 
     
     
         7 . The antibody of  claim 5 , wherein the HVR-H1 comprises the amino acid sequence of SEQ ID NO:1, the HVR-L1 comprises the amino acid sequence of SEQ ID NO:6, the HVR-L2 comprises the amino acid sequence of SEQ ID NO:11, and the HVR-L3 comprises the amino acid sequence of SEQ ID NO:15. 
     
     
         8 . The antibody of  claim 1 , wherein the HVR-H1 comprises the amino acid sequence of SEQ ID NO:1, the HVR-H2 comprises the amino acid sequence of SEQ ID NO:4; the HVR-H3 comprises the amino acid sequence of SEQ ID NO:5; the HVR-L1 comprises the amino acid sequence of SEQ ID NO:6, the HVR-L2 comprises the amino acid sequence of SEQ ID NO:11, and the HVR-L3 comprises the amino acid sequence of SEQ ID NO:15. 
     
     
         9 - 10 . (canceled) 
     
     
         11 . The antibody of  claim 1 , further comprising at least one framework selected from a human VH Acceptor 2 framework and a human VL kappa subgroup I consensus framework. 
     
     
         12 - 13 . (canceled) 
     
     
         14 . The antibody of  claim 1 , wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:20, and the light chain variable domain comprises the amino acid sequence of SEQ ID NO:22. 
     
     
         15 - 18 . (canceled) 
     
     
         19 . The antibody of  claim 1 , wherein the antibody is an antibody fragment selected from a Fab, Fab′-SH, Fv, scFv, or (Fab′)2 fragment. 
     
     
         20 . The antibody of  claim 1 , wherein the antibody is human, humanized, or chimeric. 
     
     
         21 . A method of inhibiting Notch2 activity, the method comprising exposing a cell that expresses Notch2 to the antibody of  claim 1 . 
     
     
         22 . A method of treating a disorder associated with increased expression or activity of Notch2, the method comprising administering to a subject in need thereof an effective amount of the antibody of  claim 1 . 
     
     
         23 . The method of  claim 22 , wherein the disorder associated with increased expression or activity of Notch 2 is a B-cell malignancy. 
     
     
         24 . The method of  claim 22 , wherein the disorder associated with increased expression or activity of Notch 2 is melanoma.