Anti-prlr antibody-drug conjugates (adc) and uses thereof

Abstract

Provided are antibody drug conjugates that bind PRLR, in particular human PRLR, their methods of making, and uses thereof.

What is claimed is: 
     
         1 . An antibody-drug conjugate (ADC) comprising the structure of Formula (X) 
       
         
           
           
               
               
           
         
         (X), or a salt thereof, 
         wherein Ab comprises an anti-PRLR antibody comprising: 
         i. a heavy chain variable region comprising a CDRH1 sequence comprising SEQ ID NO: 3, a CDRH2 sequence comprising SEQ ID NO: 4, and a CDRH3 sequence comprising SEQ ID NO: 5; 
         ii. a light chain variable region comprising a CDRL1 sequence comprising SEQ ID NO: 8, a CDRL2 sequence comprising SEQ ID NO: 9, and a CDRL3 sequence comprising SEQ ID NO: 10; 
         iii. a mutation comprising S239C in a heavy chain constant region, wherein the numbering is in accordance with Kabat; and 
         iv. wherein n is about 2. 
       
     
     
         2 . The ADC of  claim 1 , wherein the heavy chain variable region comprises SEQ ID NO: 2 and the light chain variable region comprises SEQ ID NO: 7. 
     
     
         3 . The ADC of  claim 1 , comprising a full heavy chain comprising SEQ ID NO: 1, and a full light chain comprising SEQ ID NO: 6. 
     
     
         4 . The ADC of  claim 1 , wherein the anti-PRLR antibody comprises an IgG1 isotype. 
     
     
         5 . The ADC of  claim 1 , wherein the heavy chain constant region of the anti-PRLR antibody either lacks a C-terminal lysine or comprises an amino acid other than lysine at a C-terminus of the heavy chain constant region. 
     
     
         6 . The ADC of  claim 1 , wherein
 the heavy chain variable region comprises SEQ ID NO: 2, and   the light chain variable region comprises SEQ ID NO: 7.   
     
     
         7 . The ADC of  claim 6 , comprising a full heavy chain comprising SEQ ID NO: 1, and a full light chain comprising SEQ ID NO: 6. 
     
     
         8 . The ADC of  claim 6 , wherein the anti-PRLR antibody comprises an IgG1 isotype. 
     
     
         9 . The ADC of  claim 6 , wherein the heavy chain constant region of the anti-PRLR antibody either lacks a C-terminal lysine or comprises an amino acid other than lysine at a C-terminus of the heavy chain constant region. 
     
     
         10 . The ADC of  claim 1 , wherein the heavy chain comprises SEQ ID NO: 1 and the light chain comprises SEQ ID NO: 6. 
     
     
         11 . The ADC of  claim 10 , wherein the anti-PRLR antibody is a humanized antibody. 
     
     
         12 . An antibody-drug conjugate (ADC) comprising the structure of Formula (IX) 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein D comprises a pyrrolobenzodiazepine (PBD) dimer; Ab is an anti-prolactin receptor (PRLR) antibody, Y is Val, Z is Ala, and q is 1, 2, 3, 4, 5, 6, 7, or 8, and wherein the anti-PRLR antibody comprises: 
         i. a heavy chain variable region comprising a CDRH1 sequence comprising SEQ ID NO: 3, a CDRH2 sequence comprising SEQ ID NO: 4, and a CDRH3 sequence comprising SEQ ID NO: 5; 
         ii. a light chain variable region comprising a CDRL1 sequence comprising SEQ ID NO: 8, a CDRL2 sequence comprising SEQ ID NO: 9, and a CDRL3 sequence comprising SEQ ID NO: 10; 
         iii. a mutation comprising S239C in a heavy chain constant region, wherein the numbering is in accordance with Kabat; and 
         iv. wherein n is about 2. 
       
     
     
         13 . The ADC of  claim 12 , wherein q is 5. 
     
     
         14 . The ADC of  claim 12 , wherein the heavy chain variable region comprises SEQ ID NO: 2, and the light chain variable region comprises SEQ ID NO: 7. 
     
     
         15 . The ADC of  claim 14 , wherein the heavy chain comprises SEQ ID NO: 1, and the light chain comprises SEQ ID NO: 6. 
     
     
         16 . The ADC of  claim 12 , wherein the anti-PRLR antibody comprises an IgG1 isotype. 
     
     
         17 . The ADC of  claim 12 , wherein the heavy chain constant region of the anti-PRLR antibody either lacks a C-terminal lysine or comprises an amino acid other than lysine at a C-terminus of the heavy chain constant region.