Anti-lgr5 antibodies and immunoconjugates

Abstract

The invention provides anti-LgR5 antibodies and immunoconjugates and methods of using the same.

1 . An isolated antibody that binds to LgR5, wherein the antibody comprises:
 a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 30, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 31, HVR-H3 comprising the amino acid sequence of SEQ ID NO: 32, HVR-L1 comprising the amino acid sequence of SEQ ID NO: 27, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 28, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 29; or   b) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 60, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 61, HVR-H3 comprising the amino acid sequence of SEQ ID NO: 62, HVR-L1 comprising the amino acid sequence of SEQ ID NO: 57, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 58, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59.   
     
     
         2 . The antibody of  claim 1 , which is a monoclonal antibody. 
     
     
         3 . The antibody of  claim 1 , which is a human, humanized, or chimeric antibody. 
     
     
         4 . The antibody of  claim 1 , which is an antibody fragment that binds LgR5. 
     
     
         5 . The antibody of  claim 1 , wherein LgR5 is human LgR5 of SEQ ID NO: 67. 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . The antibody of  claim 7 , wherein the antibody comprises:
 a) heavy chain framework FR3 sequence of SEQ ID NO: 40;   b) heavy chain framework FR3 sequence of SEQ ID NO: 41;   c) heavy chain framework FR3 sequence of SEQ ID NO: 42; or   d) heavy chain framework FR3 sequence of SEQ ID NO: 43.   
     
     
         9 . The antibody of  claim 1 , wherein the antibody comprises:
 HVR-H1 comprising the amino acid sequence of SEQ ID NO: 30, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 31, HVR-H3 comprising the amino acid sequence of SEQ ID NO: 32, HVR-L1 comprising the amino acid sequence of SEQ ID NO: 27, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 28, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 29.   
     
     
         10 . The antibody of  claim 1 , wherein the antibody comprises:
 HVR-H1 comprising the amino acid sequence of SEQ ID NO: 60, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 61, HVR-H3 comprising the amino acid sequence of SEQ ID NO: 62, HVR-L1 comprising the amino acid sequence of SEQ ID NO: 57, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 58, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 59.   
     
     
         11 . The antibody of  claim 9 , wherein the antibody further comprises a light chain framework FR3 sequence of SEQ ID NO: 35. 
     
     
         12 . The antibody of  claim 1 , wherein the antibody comprises:
 a) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 6;   b) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 5;   c) a VH sequence as in (a) and a VL sequence as in (b);   d) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8;   e) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7;   f) a VH sequence as in (d) and a VL sequence as in (e);   g) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 10;   h) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 9;   i) a VH sequence as in (g) and a VL sequence as in (h);   j) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 12;   k) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 11;   l) a VH sequence as in (j) and a VL sequence as in (k);   m) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 14;   n) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 13;   o) a VH sequence as in (m) and a VL sequence as in (n);   p) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16;   q) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15;   r) a VH sequence as in (p) and a VL sequence as in (q);   s) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 18;   t) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17;   u) a VH sequence as in (s) and a VL sequence as in (t);   v) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 20;   w) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19;   x) a VH sequence as in (v) and a VL sequence as in (w);   y) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 26;   z) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 25; or   aa) a VH sequence as in (y) and a VL sequence as in (z).   
     
     
         13 . The antibody of  claim 12 , comprising a VH sequence selected from SEQ ID NOs: 6, 8, 10, 12, 14, 16, 18, 20, and 26. 
     
     
         14 . The antibody of  claim 12 , comprising a VL sequence selected from SEQ ID NOs: 5, 7, 9, 11, 13, 15, 17, 19, and 25. 
     
     
         15 . An antibody comprising:
 a) a VH sequence of SEQ ID NO: 6 and a VL sequence of SEQ ID NO: 5;   b) a VH sequence of SEQ ID NO: 8 and a VL sequence of SEQ ID NO: 7;   c) a VH sequence of SEQ ID NO: 10 and a VL sequence of SEQ ID NO: 9;   d) a VH sequence of SEQ ID NO: 12 and a VL sequence of SEQ ID NO: 11;   e) a VH sequence of SEQ ID NO: 14 and a VL sequence of SEQ ID NO: 13;   f) a VH sequence of SEQ ID NO: 16 and a VL sequence of SEQ ID NO: 15;   g) a VH sequence of SEQ ID NO: 18 and a VL sequence of SEQ ID NO: 17;   h) a VH sequence of SEQ ID NO: 20 and a VL sequence of SEQ ID NO: 19; or   i) a VH sequence of SEQ ID NO: 26 and a VL sequence of SEQ ID NO: 25.   
     
     
         16 . The antibody of  claim 1 , which is an IgG1, IgG2a or IgG2b antibody. 
     
     
         17 - 59 . (canceled) 
     
     
         60 . The antibody of  claim 1 , wherein the antibody binds an epitope within amino acids 22-323 of SEQ ID NO: 67. 
     
     
         61 . The antibody of  claim 1 , wherein the antibody binds an epitope within amino acids 22-123 of SEQ ID NO: 67. 
     
     
         62 . The antibody of  claim 1 , wherein the antibody binds to LgR5 with an affinity of ≦5 nM. 
     
     
         63 . The antibody of  claim 13 , comprising a VL sequence selected from SEQ ID NOs: 5, 7, 9, 11, 13, 15, 17, 19, and 25.