Predicting tumor response to anti-erbb3 antibodies

Abstract

A diagnostic method for predicting quantitatively whether a human tumor will be sensitive or resistant to treatment with an ERBB3 inhibitor, e.g, an anti-ERBB3 antibody, is disclosed. The method is based on measurement of NRG1 expression at the RNA level, or at the protein level, in a tissue sample from the tumor.

1 . A method of treating a tumor with an anti-ERBB3 antibody, the method comprising administering the anti-ERBB3 antibody to a subject with a tumor likely to be sensitive to the antibody, wherein the subject is identified by:
 (a) measuring NRG1 gene expression in a tissue sample from the tumor, thereby determining an NRG1 score, wherein the expression of one or more genes is measured in addition to NRG1 and the one or more genes does not include ErbB1, ErbB2, ErbB3, or betacellulin (BTC); and   (b) determining that the NRG1 score is equal to or above a threshold score defined by a threshold determination analysis, indicating that the tumor is likely to be responsive to treatment with an anti-ERBB3 antibody.   
     
     
         2 . The method of  claim 1 , wherein the anti-ERBB3 antibody inhibits or prevents binding of NRG1 to ERBB3. 
     
     
         3 . The method of  claim 1 , wherein the anti-ERBB3 antibody inhibits or prevents dimerization of ERBB3 without inhibiting binding of NRG1 to ERBB3. 
     
     
         4 . The method of  claim 2 , wherein the anti-ERBB3 antibody is selected from the group consisting of:
 (a) (i) an immunoglobulin heavy chain variable region comprising a CDR H1  comprising the amino acid sequence of SEQ ID NO: 1, a CDR H2  comprising the amino acid sequence of SEQ ID NO: 2, and a CDR H3  comprising the amino acid sequence of SEQ ID NO: 3; and
 (ii) an immunoglobulin light chain variable region comprising a CDR L1  comprising the amino acid sequence of SEQ ID NO: 4, a CDR L2  comprising the amino acid sequence of SEQ ID NO: 5, and a CDR L3  comprising the amino acid sequence of SEQ ID NO: 6; 
   (b) (i) an immunoglobulin heavy chain variable region comprising a CDR H1  comprising the amino acid sequence of SEQ ID NO: 11, a CDR H2  comprising the amino acid sequence of SEQ ID NO: 12, and a CDR H3  comprising the amino acid sequence of SEQ ID NO: 13; and
 (ii) an immunoglobulin light chain variable region comprising a CDR L1  comprising the amino acid sequence of SEQ ID NO: 14, a CDR L2  comprising the amino acid sequence of SEQ ID NO: 15, and a CDR L3  comprising the amino acid sequence of SEQ ID NO: 16; 
   (c) (i) an immunoglobulin heavy chain variable region comprising a CDR H1  comprising the amino acid sequence of SEQ ID NO: 40, a CDR H2  comprising the amino acid sequence of SEQ ID NO: 41, and a CDR H3  comprising the amino acid sequence of SEQ ID NO: 42; and
 (ii) an immunoglobulin light chain variable region comprising a CDR L1  comprising the amino acid sequence of SEQ ID NO: 14, a CDR L2  comprising the amino acid sequence of SEQ ID NO: 15, and a CDR L3  comprising the amino acid sequence of SEQ ID NO: 16; 
   (d) (i) an immunoglobulin heavy chain variable region comprising a CDR H1  comprising the amino acid sequence of SEQ ID NO: 47, a CDR H2  comprising the amino acid sequence of SEQ ID NO: 48, and a CDR H3  comprising the amino acid sequence of SEQ ID NO: 49; and
 (ii) an immunoglobulin light chain variable region comprising a CDR L1  comprising the amino acid sequence of SEQ ID NO: 50, a CDR L2  comprising the amino acid sequence of SEQ ID NO: 51, and a CDR L3  comprising the amino acid sequence of SEQ ID NO: 52; and 
   (e) (i) an immunoglobulin heavy chain variable region comprising a CDR H1  comprising the amino acid sequence of SEQ ID NO: 57, a CDR H2  comprising the amino acid sequence of SEQ ID NO: 58, and a CDR H3  comprising the amino acid sequence of SEQ ID NO: 42; and
 (ii) an immunoglobulin light chain variable region comprising a CDR L1  comprising the amino acid sequence of SEQ ID NO: 14, a CDR L2  comprising the amino acid sequence of SEQ ID NO: 15, and a CDR L3  comprising the amino acid sequence of SEQ ID NO: 16; 
   (f) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7, and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 8;   (g) an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 9, and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 10;   (h) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 17, and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 18;   (i) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 43, and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 44;   (j) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53, and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 54; and   (k) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59, and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 60.   
     
     
         5 . The method of  claim 3 , wherein the anti-ERBB3 antibody is selected from the group consisting of:
 (a) (i) an immunoglobulin heavy chain variable region comprising a CDR H1  comprising the amino acid sequence of SEQ ID NO: 21, a CDR H2  comprising the amino acid sequence of SEQ ID NO: 22, and a CDR H3  comprising the amino acid sequence of SEQ ID NO: 23; and
 (ii) an immunoglobulin light chain variable region comprising a CDR L1  comprising the amino acid sequence of SEQ ID NO: 24, a CDR L2  comprising the amino acid sequence of SEQ ID NO: 25, and a CDR L3  comprising the amino acid sequence of SEQ ID NO: 26; 
   (b) (i) an immunoglobulin heavy chain variable region comprising a CDR H1  comprising the s amino acid sequence of SEQ ID NO: 31, a CDR H2  comprising the amino acid sequence of SEQ ID NO: 32, and a CDR H3  comprising the amino acid sequence of SEQ ID NO: 33; and
 (ii) an immunoglobulin light chain variable region comprising a CDR L1  comprising the amino acid sequence of SEQ ID NO: 34, a CDR L2  comprising the amino acid sequence of SEQ ID NO: 15, and a CDR L3  comprising the amino acid sequence of SEQ ID NO: 35; 
   (c) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 27, and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 28; and   (d) an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 36, and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 37.   
     
     
         6 . The method of  claim 2 , wherein the anti-ERBB3 antibody comprises (i) an immunoglobulin heavy chain variable region comprising a CDR H1  comprising the amino acid sequence of SEQ ID NO: 1, a CDR H2  comprising the amino acid sequence of SEQ ID NO: 2, and a CDR H3  comprising the amino acid sequence of SEQ ID NO: 3; and (ii) an immunoglobulin light chain variable region comprising a CDR L1  comprising the amino acid sequence of SEQ ID NO: 4, a CDR L2  comprising the amino acid sequence of SEQ ID NO: 5, and a CDR L3  comprising the amino acid sequence of SEQ ID NO: 6. 
     
     
         7 . The method of  claim 2 , wherein the anti-ERBB3 antibody comprises an immunoglobulin heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7, and an immunoglobulin light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. 
     
     
         8 . The method of  claim 2 , wherein the anti-ERBB3 antibody comprises an immunoglobulin heavy chain comprising the amino acid sequence of SEQ ID NO: 9, and an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO: 10. 
     
     
         9 . The method of  claim 1 , wherein the step of measuring NRG1 gene expression is performed by measuring the level of NRG1 protein. 
     
     
         10 . The method of  claim 1 , wherein the step of measuring NRG1 gene expression is performed by measuring the level of mRNA encoding NRG1 protein. 
     
     
         11 . The method of  claim 1 , wherein the threshold determination analysis comprises a receiver operator characteristic curve analysis. 
     
     
         12 . The method of  claim 1 , wherein the tumor is a solid tumor. 
     
     
         13 . The method of  claim 1 , wherein the expression of one or more other genes measured in addition to NRG1 serves as a control or standard for data normalization. 
     
     
         14 . The method of  claim 1 , wherein the expression of one or more other genes measured in addition to NRG1 is used to classify the tumor as likely to be responsive to treatment with an anti-ERBB3 antibody.