US2018186871A1PendingUtilityA1

Il-11 antibodies

Assignee: SINGAPORE HEALTH SERV PTE LTDPriority: Dec 16, 2016Filed: Dec 15, 2017Published: Jul 5, 2018
Est. expiryDec 16, 2036(~10.4 yrs left)· nominal 20-yr term from priority
C07K 2317/515A61P 11/00A61P 17/00C07K 2319/75C07K 2317/24C07K 14/7155A61P 35/00C07K 2317/33A61P 9/00A61K 2039/505C07K 2317/92C07K 2317/56C07K 2317/52A61P 1/16A61P 17/02A61K 47/6845C07K 2317/21C07K 16/244C07K 2317/565A61P 13/12C07K 2317/76A61P 27/02C07K 14/5431C07K 2317/622A61P 43/00C07K 2317/20G01N 2333/5431G01N 33/6869G01N 2800/52
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Claims

Abstract

IL-11 antibodies are disclosed. Also disclosed are compositions comprising the IL-11 antibodies, and methods using the IL-11 antibodies.

Claims

exact text as granted — not AI-modified
1 - 99 . (canceled) 
     
     
         100 . An antibody or antigen binding fragment, optionally isolated, which is capable of binding to IL-11, comprising a light chain variable region sequence and a heavy chain variable region sequence, wherein:
 the light chain variable region sequence has at least 85% sequence identity to the light chain variable region sequence of SEQ ID NO:342, and   the heavy chain variable region sequence has at least 85% sequence identity to the heavy chain variable region sequence of SEQ ID NO:382.   
     
     
         101 . The antibody or antigen binding fragment according to  claim 100 , wherein:
 the light chain variable region sequence has at least 90% sequence identity to the light chain variable region sequence of SEQ ID NO:342, and   the heavy chain variable region sequence has at least 90% sequence identity to the heavy chain variable region sequence of SEQ ID NO:382.   
     
     
         102 . The antibody or antigen binding fragment according to  claim 100 , wherein the light chain variable region sequence comprises the following CDRs: 
       
         
           
                 
                 
               
                     
                   i) LC-CDR1: 
                 
                 
               
                   (SEQ ID NO: 110) 
                 
                 
                 
               
                     
                   SSDVGAYNY, 
                 
                 
               
                   (SEQ ID NO: 107) 
                 
                 
                 
               
                     
                   SSDVGGYNY 
                 
                     
                   or 
                 
                 
               
                   (SEQ ID NO: 330) 
                 
                 
                 
               
                     
                   SSDVAGYNY; 
                 
                     
                     
                 
                     
                   ii) LC-CDR2: 
                 
                 
               
                   (SEQ ID NO: 108) 
                 
                 
                 
               
                     
                   DVS, 
                 
                 
               
                   (SEQ ID NO: 291) 
                 
                 
                 
               
                     
                   DVN 
                 
                     
                   or 
                 
                 
               
                   (SEQ ID NO: 123) 
                 
                 
                 
               
                     
                   DVT; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   iii) LC-CDR3: 
                 
                 
               
                   (SEQ ID NO: 131) 
                 
                 
                 
               
                     
                   CSYAGSYTWV 
                 
                     
                   or 
                 
                 
               
                   (SEQ ID NO: 336) 
                 
                 
                 
               
                     
                   CSYAGRYTWM; 
                 
             
                
               
            
             
                
               
            
             
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
               
            
           
         
         and wherein the heavy chain variable region sequence comprises the following CDRs 
       
       
         
           
                 
                 
               
                     
                   iv) HC-CDR1: 
                 
                 
               
                   (SEQ ID NO: 190) 
                 
                 
                 
               
                     
                   GFTFSSYA 
                 
                     
                   or 
                 
                 
               
                   (SEQ ID NO: 186) 
                 
                 
                 
               
                     
                   GFTFSSYG; 
                 
                     
                     
                 
                     
                   v) HC-CDR2: 
                 
                 
               
                   (SEQ ID NO: 184) 
                 
                 
                 
               
                     
                   ISYDGSNK; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   vi) HC-CDR3: 
                 
                 
               
                   (SEQ ID NO: 199) 
                 
                 
                 
               
                     
                   ARIMGYDYGDYDVVDY 
                 
                     
                   or 
                 
                 
               
                   (SEQ ID NO: 187) 
                 
                 
                 
               
                     
                   AKIGATDPLDY. 
                 
             
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
               
            
           
         
       
     
     
         103 . The antibody or antigen binding fragment according to  claim 100 , wherein the light chain variable region sequence comprises the following CDRs: 
       
         
           
                 
                 
               
                     
                   i) LC-CDR1: 
                 
                 
               
                   (SEQ ID NO: 110) 
                 
                 
                 
               
                     
                   SSDVGAYNY; 
                 
                     
                     
                 
                     
                   ii) LC-CDR2: 
                 
                 
               
                   (SEQ ID NO: 108) 
                 
                 
                 
               
                     
                   DVS; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   iii) LC-CDR3: 
                 
                 
               
                   (SEQ ID NO: 131) 
                 
                 
                 
               
                     
                   CSYAGSYTWV; 
                 
             
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
         and wherein the heavy chain variable region sequence comprises the following CDRs 
       
       
         
           
                 
                 
               
                     
                   iv) HC-CDR1: 
                 
                 
               
                   (SEQ ID NO: 190) 
                 
                 
                 
               
                     
                   GFTFSSYA; 
                 
                     
                     
                 
                     
                   v) HC-CDR2: 
                 
                 
               
                   (SEQ ID NO: 184) 
                 
                 
                 
               
                     
                   ISYDGSNK; 
                 
                     
                     
                 
                     
                   vi) HC-CDR3: 
                 
                 
               
                   (SEQ ID NO: 199) 
                 
                 
                 
               
                     
                   ARIMGYDYGDYDVVDY. 
                 
             
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
       
     
     
         104 . The antibody or antigen binding fragment according to  claim 100 , wherein the light chain variable region sequence comprises the following CDRs: 
       
         
           
                 
                 
               
                     
                   i) LC-CDR1: 
                 
                 
               
                   (SEQ ID NO: 107) 
                 
                 
                 
               
                     
                   SSDVGGYNY; 
                 
                     
                     
                 
                     
                   ii) LC-CDR2: 
                 
                 
               
                   (SEQ ID NO: 291) 
                 
                 
                 
               
                     
                   DVN; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   iii) LC-CDR3: 
                 
                 
               
                   (SEQ ID NO: 336) 
                 
                 
                 
               
                     
                   CSYAGRYTWM; 
                 
             
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
         and wherein the heavy chain variable region sequence comprises the following CDRs 
       
       
         
           
                 
                 
               
                     
                   iv) HC-CDR1: 
                 
                 
               
                   (SEQ ID NO: 186) 
                 
                 
                 
               
                     
                   GFTFSSYG; 
                 
                     
                     
                 
                     
                   v) HC-CDR2: 
                 
                 
               
                   (SEQ ID NO: 184) 
                 
                 
                 
               
                     
                   ISYDGSNK; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   vi) HC-CDR3: 
                 
                 
               
                   (SEQ ID NO: 187) 
                 
                 
                 
               
                     
                   AKIGATDPLDY. 
                 
             
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
       
     
     
         105 . The antibody or antigen binding fragment according to  claim 100 , wherein the light chain variable region sequence comprises the following CDRs: 
       
         
           
                 
                 
               
                     
                   i) LC-CDR1: 
                 
                 
               
                   (SEQ ID NO: 330) 
                 
                 
                 
               
                     
                   SSDVAGYNY; 
                 
                     
                     
                 
                     
                   ii) LC-CDR2: 
                 
                 
               
                   (SEQ ID NO: 123) 
                 
                 
                 
               
                     
                   DVT 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   iii) LC-CDR3: 
                 
                 
               
                   (SEQ ID NO: 131) 
                 
                 
                 
               
                     
                   CSYAGSYTWV; 
                 
             
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
         and wherein the heavy chain variable region sequence comprises the following CDRs 
       
       
         
           
                 
                 
               
                     
                   iv) HC-CDR1: 
                 
                 
               
                   (SEQ ID NO: 186) 
                 
                 
                 
               
                     
                   GFTFSSYG; 
                 
                     
                     
                 
                     
                   v) HC-CDR2: 
                 
                 
               
                   (SEQ ID NO: 184) 
                 
                 
                 
               
                     
                   ISYDGSNK; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   vi) HC-CDR3: 
                 
                 
               
                   (SEQ ID NO: 187) 
                 
                 
                 
               
                     
                   AKIGATDPLDY. 
                 
             
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
       
     
     
         106 . The antibody or antigen binding fragment according to  claim 100 , which is capable of inhibiting IL-11 trans signalling. 
     
     
         107 . The antibody or antigen binding fragment according  claim 100 , conjugated to a drug moiety or a detectable moiety. 
     
     
         108 . A method of treating fibrosis or a disease/disorder characterised by fibrosis, comprising administering an antibody or antigen binding fragment to a subject suffering from fibrosis or a disease/disorder characterised by fibrosis, wherein the antibody or antigen binding fragment is capable of binding to IL-11, and comprises a light chain variable region sequence and a heavy chain variable region sequence, wherein:
 the light chain variable region sequence has at least 85% sequence identity to the light chain variable region sequence of SEQ ID NO:342, and   the heavy chain variable region sequence has at least 85% sequence identity to the heavy chain variable region sequence of SEQ ID NO:382.   
     
     
         109 . The method according to  claim 108 , wherein:
 the light chain variable region sequence has at least 90% sequence identity to the light chain variable region sequence of SEQ ID NO:342, and   the heavy chain variable region sequence has at least 90% sequence identity to the heavy chain variable region sequence of SEQ ID NO:382.   
     
     
         110 . The method according to  claim 108 , wherein the light chain variable region sequence comprises the following CDRs: 
       
         
           
                 
                 
               
                     
                   i) LC-CDR1: 
                 
                 
               
                   (SEQ ID NO: 110) 
                 
                 
                 
               
                     
                   SSDVGAYNY, 
                 
                 
               
                   (SEQ ID NO: 107) 
                 
                 
                 
               
                     
                   SSDVGGYNY 
                 
                     
                   or 
                 
                 
               
                   (SEQ ID NO: 330) 
                 
                 
                 
               
                     
                   SSDVAGYNY; 
                 
                     
                     
                 
                     
                   ii) LC-CDR2: 
                 
                 
               
                   (SEQ ID NO: 108) 
                 
                 
                 
               
                     
                   DVS, 
                 
                 
               
                   (SEQ ID NO: 291) 
                 
                 
                 
               
                     
                   DVN 
                 
                     
                   or 
                 
                 
               
                   (SEQ ID NO: 123) 
                 
                 
                 
               
                     
                   DVT; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   iii) LC-CDR3: 
                 
                 
               
                   (SEQ ID NO: 131) 
                 
                 
                 
               
                     
                   CSYAGSYTWV 
                 
                     
                   or 
                 
                 
               
                   (SEQ ID NO: 336) 
                 
                 
                 
               
                     
                   CSYAGRYTWM; 
                 
             
                
               
            
             
                
               
            
             
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
               
            
           
         
         and wherein the heavy chain variable region sequence comprises the following CDRs 
       
       
         
           
                 
                 
               
                     
                   iv) HC-CDR1: 
                 
                 
               
                   (SEQ ID NO: 190) 
                 
                 
                 
               
                     
                   GFTFSSYA 
                 
                     
                   or 
                 
                     
                     
                 
                 
               
                   (SEQ ID NO: 186) 
                 
                 
                 
               
                     
                   GFTFSSYG; 
                 
                     
                     
                 
                     
                   v) HC-CDR2: 
                 
                 
               
                   (SEQ ID NO: 184) 
                 
                 
                 
               
                     
                   ISYDGSNK; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   vi) HC-CDR3: 
                 
                 
               
                   (SEQ ID NO: 199) 
                 
                 
                 
               
                     
                   ARIMGYDYGDYDVVDY 
                 
                     
                   or 
                 
                     
                     
                 
                 
               
                   (SEQ ID NO: 187) 
                 
                 
                 
               
                     
                   AKIGATDPLDY. 
                 
             
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
       
     
     
         111 . The method according to  claim 108 , wherein the light chain variable region sequence comprises the following CDRs: 
       
         
           
                 
                 
               
                     
                   i) LC-CDR1: 
                 
                 
               
                   (SEQ ID NO: 110) 
                 
                 
                 
               
                     
                   SSDVGAYNY; 
                 
                     
                     
                 
                     
                   ii) LC-CDR2: 
                 
                 
               
                   (SEQ ID NO: 108) 
                 
                 
                 
               
                     
                   DVS; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   iii) LC-CDR3: 
                 
                 
               
                   (SEQ ID NO: 131) 
                 
                 
                 
               
                     
                   CSYAGSYTWV; 
                 
             
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
         and wherein the heavy chain variable region sequence comprises the following CDRs 
       
       
         
           
                 
                 
               
                     
                   iv) HC-CDR1: 
                 
                 
               
                   (SEQ ID NO: 190) 
                 
                 
                 
               
                     
                   GFTFSSYA; 
                 
                     
                     
                 
                     
                   v) HC-CDR2: 
                 
                 
               
                   (SEQ ID NO: 184) 
                 
                 
                 
               
                     
                   ISYDGSNK; 
                 
                     
                     
                 
                     
                   vi) HC-CDR3: 
                 
                 
               
                   (SEQ ID NO: 199) 
                 
                 
                 
               
                     
                   ARIMGYDYGDYDVVDY. 
                 
             
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
       
     
     
         112 . The method according to  claim 108 , wherein the light chain variable region sequence comprises the following CDRs: 
       
         
           
                 
                 
               
                     
                   i) LC-CDR1: 
                 
                 
               
                   (SEQ ID NO: 107) 
                 
                 
                 
               
                     
                   SSDVGGYNY; 
                 
                     
                     
                 
                     
                   ii) LC-CDR2: 
                 
                 
               
                   (SEQ ID NO: 291) 
                 
                 
                 
               
                     
                   DVN; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   iii) LC-CDR3: 
                 
                 
               
                   (SEQ ID NO: 336) 
                 
                 
                 
               
                     
                   CSYAGRYTWM; 
                 
             
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
         and wherein the heavy chain variable region sequence comprises the following CDRs 
       
       
         
           
                 
                 
               
                     
                   iv) HC-CDR1: 
                 
                 
               
                   (SEQ ID NO: 186) 
                 
                 
                 
               
                     
                   GFTFSSYG; 
                 
                     
                     
                 
                     
                   v) HC-CDR2: 
                 
                 
               
                   (SEQ ID NO: 184) 
                 
                 
                 
               
                     
                   ISYDGSNK; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   vi) HC-CDR3: 
                 
                 
               
                   (SEQ ID NO: 187) 
                 
                 
                 
               
                     
                   AKIGATDPLDY. 
                 
             
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
       
     
     
         113 . The method according to  claim 108 , wherein the light chain variable region sequence comprises the following CDRs: 
       
         
           
                 
                 
               
                     
                   i) LC-CDR1: 
                 
                 
               
                   (SEQ ID NO: 330) 
                 
                 
                 
               
                     
                   SSDVAGYNY; 
                 
                     
                     
                 
                     
                   ii) LC-CDR2: 
                 
                 
               
                   (SEQ ID NO: 123) 
                 
                 
                 
               
                     
                   DVT; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   iii) LC-CDR3: 
                 
                 
               
                   (SEQ ID NO: 131) 
                 
                 
                 
               
                     
                   CSYAGSYTWV; 
                 
             
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
         and wherein the heavy chain variable region sequence comprises the following CDRs 
       
       
         
           
                 
                 
               
                     
                   iv) HC-CDR1: 
                 
                 
               
                   (SEQ ID NO: 186) 
                 
                 
                 
               
                     
                   GFTFSSYG; 
                 
                     
                     
                 
                     
                   v) HC-CDR2: 
                 
                 
               
                   (SEQ ID NO: 184) 
                 
                 
                 
               
                     
                   ISYDGSNK; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   vi) HC-CDR3: 
                 
                 
               
                   (SEQ ID NO: 187) 
                 
                 
                 
               
                     
                   AKIGATDPLDY. 
                 
             
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
       
     
     
         114 . A method of treating cancer, comprising administering an antibody or antigen binding fragment to a subject suffering from cancer, wherein the antibody or antigen binding fragment is capable of binding to IL-11, and comprises a light chain variable region sequence and a heavy chain variable region sequence, wherein:
 the light chain variable region sequence has at least 85% sequence identity to the light chain variable region sequence of SEQ ID NO:342, and   the heavy chain variable region sequence has at least 85% sequence identity to the heavy chain variable region sequence of SEQ ID NO:382.   
     
     
         115 . The method according to  claim 114 , wherein:
 the light chain variable region sequence has at least 90% sequence identity to the light chain variable region sequence of SEQ ID NO:342, and   the heavy chain variable region sequence has at least 90% sequence identity to the heavy chain variable region sequence of SEQ ID NO:382.   
     
     
         116 . The method according to  claim 114 , wherein the light chain variable region sequence comprises the following CDRs: 
       
         
           
                 
                 
               
                     
                   i) LC-CDR1: 
                 
                 
               
                   (SEQ ID NO: 110) 
                 
                 
                 
               
                     
                   SSDVGAYNY, 
                 
                     
                     
                 
                 
               
                   (SEQ ID NO: 107) 
                 
                 
                 
               
                     
                   SSDVGGYNY 
                 
                     
                   or 
                 
                     
                     
                 
                 
               
                   (SEQ ID NO: 330) 
                 
                 
                 
               
                     
                   SSDVAGYNY; 
                 
                     
                     
                 
                     
                   ii) LC-CDR2: 
                 
                 
               
                   (SEQ ID NO: 108) 
                 
                 
                 
               
                     
                   DVS, 
                 
                     
                     
                 
                 
               
                   (SEQ ID NO: 291) 
                 
                 
                 
               
                     
                   DVN 
                 
                     
                   or 
                 
                 
               
                   (SEQ ID NO: 123) 
                 
                 
                 
               
                     
                   DVT; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   iii) LC-CDR3: 
                 
                 
               
                   (SEQ ID NO: 131) 
                 
                 
                 
               
                     
                   CSYAGSYTWV 
                 
                     
                   or 
                 
                     
                     
                 
                 
               
                   (SEQ ID NO: 336) 
                 
                 
                 
               
                     
                   CSYAGRYTWM; 
                 
             
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
         and wherein the heavy chain variable region sequence comprises the following CDRs 
       
       
         
           
                 
                 
               
                     
                   iv) HC-CDR1: 
                 
                 
               
                   (SEQ ID NO: 190) 
                 
                 
                 
               
                     
                   GFTFSSYA 
                 
                     
                   or 
                 
                 
               
                   (SEQ ID NO: 186) 
                 
                 
                 
               
                     
                   GFTFSSYG; 
                 
                     
                     
                 
                     
                   v) HC-CDR2: 
                 
                 
               
                   (SEQ ID NO: 184) 
                 
                 
                 
               
                     
                   ISYDGSNK; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   vi) HC-CDR3: 
                 
                 
               
                   (SEQ ID NO: 199) 
                 
                 
                 
               
                     
                   ARIMGYDYGDYDVVDY 
                 
                     
                   or 
                 
                     
                     
                 
                 
               
                   (SEQ ID NO: 187) 
                 
                 
                 
               
                     
                   AKIGATDPLDY. 
                 
             
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
       
     
     
         117 . The method according to  claim 114 , wherein the light chain variable region sequence comprises the following CDRs: 
       
         
           
                 
                 
               
                     
                   i) LC-CDR1: 
                 
                 
               
                   (SEQ ID NO: 110) 
                 
                 
                 
               
                     
                   SSDVGAYNY; 
                 
                     
                     
                 
                     
                   ii) LC-CDR2: 
                 
                 
               
                   (SEQ ID NO: 108) 
                 
                 
                 
               
                     
                   DVS; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   iii) LC-CDR3: 
                 
                 
               
                   (SEQ ID NO: 131) 
                 
                 
                 
               
                     
                   CSYAGSYTWV; 
                 
             
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
         and wherein the heavy chain variable region sequence comprises the following CDRs 
       
       
         
           
                 
                 
               
                     
                   iv) HC-CDR1: 
                 
                 
               
                   (SEQ ID NO: 190) 
                 
                 
                 
               
                     
                   GFTFSSYA; 
                 
                     
                     
                 
                     
                   v) HC-CDR2: 
                 
                 
               
                   (SEQ ID NO: 184) 
                 
                 
                 
               
                     
                   ISYDGSNK; 
                 
                     
                     
                 
                     
                   vi) HC-CDR3: 
                 
                 
               
                   (SEQ ID NO: 199) 
                 
                 
                 
               
                     
                   ARIMGYDYGDYDVVDY. 
                 
             
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
       
     
     
         118 . The method according to  claim 114 , wherein the light chain variable region sequence comprises the following CDRs: 
       
         
           
                 
                 
               
                     
                   i) LC-CDR1: 
                 
                 
               
                   (SEQ ID NO: 107) 
                 
                 
                 
               
                     
                   SSDVGGYNY; 
                 
                     
                     
                 
                     
                   ii) LC-CDR2: 
                 
                 
               
                   (SEQ ID NO: 291) 
                 
                 
                 
               
                     
                   DVN; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   iii) LC-CDR3: 
                 
                 
               
                   (SEQ ID NO: 336) 
                 
                 
                 
               
                     
                   CSYAGRYTWM; 
                 
             
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
         and wherein the heavy chain variable region sequence comprises the following CDRs 
       
       
         
           
                 
                 
               
                     
                   iv) HC-CDR1: 
                 
                 
               
                   (SEQ ID NO: 186) 
                 
                 
                 
               
                     
                   GFTFSSYG; 
                 
                     
                     
                 
                     
                   v) HC-CDR2: 
                 
                 
               
                   (SEQ ID NO: 184) 
                 
                 
                 
               
                     
                   ISYDGSNK; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   vi) HC-CDR3: 
                 
                 
               
                   (SEQ ID NO: 187) 
                 
                 
                 
               
                     
                   AKIGATDPLDY. 
                 
             
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
       
     
     
         119 . The method according to  claim 114 , wherein the light chain variable region sequence comprises the following CDRs: 
       
         
           
                 
                 
               
                     
                   i) LC-CDR1: 
                 
                 
               
                   (SEQ ID NO: 330) 
                 
                 
                 
               
                     
                   SSDVAGYNY; 
                 
                     
                     
                 
                     
                   ii) LC-CDR2: 
                 
                 
               
                   (SEQ ID NO: 123) 
                 
                 
                 
               
                     
                   DVT; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   iii) LC-CDR3: 
                 
                 
               
                   (SEQ ID NO: 131) 
                 
                 
                 
               
                     
                   CSYAGSYTWV; 
                 
             
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
         and wherein the heavy chain variable region sequence comprises the following CDRs 
       
       
         
           
                 
                 
               
                     
                   iv) HC-CDR1: 
                 
                 
               
                   (SEQ ID NO: 186) 
                 
                 
                 
               
                     
                   GFTFSSYG; 
                 
                     
                     
                 
                     
                   v) HC-CDR2: 
                 
                 
               
                   (SEQ ID NO: 184) 
                 
                 
                 
               
                     
                   ISYDGSNK; 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   vi) HC-CDR3: 
                 
                 
               
                   (SEQ ID NO: 187) 
                 
                 
                 
               
                     
                   AKIGATDPLDY.

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