Anti-tigit antibodies

Abstract

Anti-TIGIT antibodies and antigen binding fragments thereof that inhibit TIGIT-mediated signalling are provided, together with combinations comprising said antibodies or antigen binding fragments thereof and methods for their use.

1 .- 52 . (canceled) 
     
     
         53 . A method of promoting a T cell activity comprising contacting a population of T cells with an antibody or antigen binding fragment thereof which binds to human TIGIT, wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable domain (VH) comprising a HCDR1, a HCDR2, and a HCDR3, and a light chain variable domain (VL) comprising a LCDR1, a LCDR2 and a LCDR3, and:
 (i) the HCDR1 comprises SEQ ID NO:16, the HCDR2 comprises SEQ ID NO:17, the HCDR3 comprises SEQ ID NO:18, the LCDR1 comprises SEQ ID NO:61, the LCDR2 comprises SEQ ID NO:62, and the LCDR3 comprises SEQ ID NO:63;   (ii) the HCDR1 comprises SEQ ID NO:4, the HCDR2 comprises SEQ ID NO:5, the HCDR3 comprises SEQ ID NO:6, the LCDR1 comprises SEQ ID NO:49, the LCDR2 comprises SEQ ID NO:50, and the LCDR3 comprises SEQ ID NO:51;   (iii) the HCDR1 comprises SEQ ID NO:7, the HCDR2 comprises SEQ ID NO:8, the HCDR3 comprises SEQ ID NO:9, the LCDR1 comprises SEQ ID NO:52, the LCDR2 comprises SEQ ID NO:53, and the LCDR3 comprises SEQ ID NO:54;   (iv) the HCDR1 comprises SEQ ID NO:10, the HCDR2 comprises SEQ ID NO:11, the HCDR3 comprises SEQ ID NO:12, the LCDR1 comprises SEQ ID NO:55, the LCDR2 comprises SEQ ID NO:56, and the LCDR3 comprises SEQ ID NO:57;   (v) the HCDR1 comprises SEQ ID NO:13, the HCDR2 comprises SEQ ID NO:14, the HCDR3 comprises SEQ ID NO:15, the LCDR1 comprises SEQ ID NO:58, the LCDR2 comprises SEQ ID NO:59, and the LCDR3 comprises SEQ ID NO:60;   (vi) the HCDR1 comprises SEQ ID NO:1, the HCDR2 comprises SEQ ID NO:2, the HCDR3 comprises SEQ ID NO:3, the LCDR1 comprises SEQ ID NO:46, the LCDR2 comprises SEQ ID NO:47, and the LCDR3 comprises SEQ ID NO:48;   (vii) the HCDR1 comprises SEQ ID NO:19, the HCDR2 comprises SEQ ID NO:20, the HCDR3 comprises SEQ ID NO:21, the LCDR1 comprises SEQ ID NO:64, the LCDR2 comprises SEQ ID NO:65, and the LCDR3 comprises SEQ ID NO:66;   (viii) the HCDR1 comprises SEQ ID NO:22, the HCDR2 comprises SEQ ID NO:23, the HCDR3 comprises SEQ ID NO:24, the LCDR1 comprises SEQ ID NO:67, the LCDR2 comprises SEQ ID NO:68, and the LCDR3 comprises SEQ ID NO:69;   (ix) the HCDR1 comprises SEQ ID NO:25, the HCDR2 comprises SEQ ID NO:26, the HCDR3 comprises SEQ ID NO:27, the LCDR1 comprises SEQ ID NO:70, the LCDR2 comprises SEQ ID NO:71, and the LCDR3 comprises SEQ ID NO:72;   (x) the HCDR1 comprises SEQ ID NO:28, the HCDR2 comprises SEQ ID NO:29, the HCDR3 comprises SEQ ID NO:30, the LCDR1 com comprises prising SEQ ID NO:73, the LCDR2 comprises SEQ ID NO:74, and the LCDR3 comprises SEQ ID NO:75;   (xi) the HCDR1 comprises SEQ ID NO:31, the HCDR2 comprises SEQ ID NO:32, the HCDR3 comprises SEQ ID NO:33, the LCDR1 comprises SEQ ID NO:76, the LCDR2 comprises SEQ ID NO:77, and the LCDR3 comprises SEQ ID NO:78;   (xii) the HCDR1 comprises SEQ ID NO:34, the HCDR2 comprises SEQ ID NO:35, the HCDR3 comprises SEQ ID NO:36, the LCDR1 comprises SEQ ID NO:79, the LCDR2 comprises SEQ ID NO:80, and the LCDR3 comprises SEQ ID NO:81;   (xiii) the HCDR1 comprises SEQ ID NO:37, the HCDR2 comprises SEQ ID NO:38, the HCDR3 comprises SEQ ID NO:39, the LCDR1 comprises SEQ ID NO:82, the LCDR2 comprises SEQ ID NO:83, and the LCDR3 comprises SEQ ID NO:84;   (xiv) the HCDR1 comprises SEQ ID NO:40, the HCDR2 comprises SEQ ID NO:41, the HCDR3 comprises SEQ ID NO:42, the LCDR1 comprises SEQ ID NO:85, the LCDR2 comprises SEQ ID NO:86, and the LCDR3 comprises SEQ ID NO:87;   (xv) the HCDR1 comprises SEQ ID NO:43, the HCDR2 comprises SEQ ID NO:44, the HCDR3 comprises SEQ ID NO:45, the LCDR1 comprises SEQ ID NO:88, the LCDR2 comprises SEQ ID NO:89, and the LCDR3 comprises SEQ ID NO:90;   (xvi) the HCDR1 comprises SEQ ID NO:271, the HCDR2 comprises SEQ ID NO:272, the HCDR3 comprises SEQ ID NO:273, the LCDR1 comprises SEQ ID NO:283, the LCDR2 comprises SEQ ID NO:284, and the LCDR3 comprises SEQ ID NO:285;   (xvii) the HCDR1 comprises SEQ ID NO:274, the HCDR2 comprises SEQ ID NO:275, the HCDR3 comprises SEQ ID NO:276, the LCDR1 comprises SEQ ID NO:286, the LCDR2 comprises SEQ ID NO:287, and the LCDR3 comprises SEQ ID NO:288; or   (xviii) the HCDR1 comprises SEQ ID NO:277, the HCDR2 comprises SEQ ID NO:278, the HCDR3 comprises SEQ ID NO:279, the LCDR1 comprises SEQ ID NO:289, the LCDR2 comprises SEQ ID NO:290, and the LCDR3 comprises SEQ ID NO:291.   
     
     
         54 . The method of  claim 53 , wherein:
 (i) the VH comprises the amino acid sequence of SEQ ID NO:211 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:212 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (ii) the VH comprises the amino acid sequence of SEQ ID NO:213 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:214 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (iii) the VH comprises the amino acid sequence of SEQ ID NO:215 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:216 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (iv) the VH comprises the amino acid sequence of SEQ ID NO:217 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:218 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (v) the VH comprises the amino acid sequence of SEQ ID NO:219 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:220 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (vi) the VH comprises the amino acid sequence of SEQ ID NO:221 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:222 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (vii) the VH comprises the amino acid sequence of SEQ ID NO:223 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:224 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (viii) the VH comprises the amino acid sequence of SEQ ID NO:225 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:226 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (ix) the VH comprises the amino acid sequence of SEQ ID NO:227 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:228 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (x) the VH comprises the amino acid sequence of SEQ ID NO:229 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:230 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (xi) the VH comprises the amino acid sequence of SEQ ID NO:231 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:232 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (xii) the VH comprises the amino acid sequence of SEQ ID NO:233 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:234 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (xiii) the VH comprises the amino acid sequence of SEQ ID NO:235 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:236 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (xiv) the VH comprises the amino acid sequence of SEQ ID NO:237 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:238 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (xv) the VH comprises the amino acid sequence of SEQ ID NO:239 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:240 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (xvi) the VH comprises the amino acid sequence of SEQ ID NO:327 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:328 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (xvii) the VH comprises the amino acid sequence of SEQ ID NO:329 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:330 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL; or   (xviii) the VH comprises the amino acid sequence of SEQ ID NO:331 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:332 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL.   
     
     
         55 . The method of promoting T cell activity according to  claim 53 , wherein: 
       
         
           
                 
                 
               
                     
                   the HCDR1 comprises SEQ ID NO: 16 
                 
                     
                   (YTFTSYYMH), 
                 
                     
                     
                 
                     
                   the HCDR2 comprises SEQ ID NO: 17 
                 
                     
                   (VIGPSGASTSYAQKFQG), 
                 
                     
                     
                 
                     
                   the HCDR3 comprises SEQ ID NO: 18 
                 
                     
                   (ARDHSDYWSGIMEV), 
                 
                     
                     
                 
                     
                   the LCDR1 comprises SEQ ID NO: 61 
                 
                     
                   (RASQSVRSSYLA), 
                 
                     
                     
                 
                     
                   the LCDR2 comprises SEQ ID NO: 62 
                 
                     
                   (GASSRAT), 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   the LCDR3 comprises SEQ ID NO: 63 
                 
                     
                   (QQYFSPPWT). 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         56 . The method of promoting T cell activity according to  claim 56 , wherein the VH comprises the amino acid sequence shown as SEQ ID NO: 221 or an amino acid sequence exhibiting at least 90%, 95%, 97%, 98% or 99% sequence identity thereto wherein all differences are located in a framework region of the VL, and the light chain variable domain comprises the amino acid sequence shown as SEQ ID NO: 222 or an amino acid sequence exhibiting at least 90%, 95%, 97%, 98% or 99% sequence identity thereto, wherein all differences are located in a framework regions of the VH. 
     
     
         57 . The method of  claim 53 , wherein the method promotes αβ T cell activity. 
     
     
         58 . The method of  claim 53 , wherein the method promotes γδ T cell activity. 
     
     
         59 . The method of  claim 53 , wherein the method is performed in vitro. 
     
     
         60 . The method of  claim 53 , wherein the method is performed in vivo in a human subject. 
     
     
         61 . The method of  claim 60 , wherein the human subject has a cancer. 
     
     
         62 . The method of  claim 60 , wherein the human subject has a viral infection. 
     
     
         63 . The method of  claim 62 , wherein the viral infection is a CMV infection. 
     
     
         64 . The method of  claim 53 , wherein the method further comprises contacting the population of T cells with one or more of an anti-PD1 antibody, an anti-PD-L1 antibody, an anti-41BB antibody, an anti-OX40 antibody, an anti-GITR antibody, and an anti-ICOS antibody. 
     
     
         65 . A method of treating a viral infection in a subject comprising administering to the subject an effective amount of an antibody or antigen-binding fragment thereof which binds to human TIGIT, wherein the antibody or antigen binding fragment thereof comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3, and a VL comprising a LCDR1, a LCDR2 and a LCDR3, wherein:
 (i) the HDCR1 comprises SEQ ID NO:16, the HDCR2 comprises SEQ ID NO:17, the HDCR3 comprises SEQ ID NO:18, the LCDR1 comprises SEQ ID NO:61, the LCDR2 comprises SEQ ID NO:62, and the LCDR3 comprises SEQ ID NO:63;   (ii) the HDCR1 comprises SEQ ID NO:4, the HDCR2 comprises SEQ ID NO:5, the HDCR3 comprises SEQ ID NO:6, the LCDR1 comprises SEQ ID NO:49, the LCDR2 comprises SEQ ID NO:50, and the LCDR3 comprises SEQ ID NO:51;   (iii) the HDCR1 comprises SEQ ID NO:7, the HDCR2 comprises SEQ ID NO:8, the HDCR3 comprises SEQ ID NO:9, the LCDR1 comprises SEQ ID NO:52, the LCDR2 comprises SEQ ID NO:53, and the LCDR3 comprises SEQ ID NO:54;   (iv) the HCDR1 comprising SEQ ID NO:10, the HDCR2 comprises SEQ ID NO:11, the HDCR3 comprises SEQ ID NO:12, the LCDR1 comprises SEQ ID NO:55, the LCDR2 comprises SEQ ID NO:56, and the LCDR3 comprises SEQ ID NO:57;   (v) the HDCR1 comprises SEQ ID NO:13, the HDCR2 comprises SEQ ID NO:14, the HDCR3 comprises SEQ ID NO:15, the LCDR1 comprises SEQ ID NO:58, the LCDR2 comprises SEQ ID NO:59, and the LCDR3 comprises SEQ ID NO:60;   (vi) the HDCR1 comprises SEQ ID NO:1, the HDCR2 comprises SEQ ID NO:2, the HDCR3 comprises SEQ ID NO:3, the LCDR1 comprises SEQ ID NO:46, the LCDR2 comprises SEQ ID NO:47, and the LCDR3 comprises SEQ ID NO:48;   (vii) the HDCR1 comprises SEQ ID NO:19, the HDCR2 comprises SEQ ID NO:20, the HDCR3 comprises SEQ ID NO:21, the LCDR1 comprises SEQ ID NO:64, the LCDR2 comprises SEQ ID NO:65, and the LCDR3 comprises SEQ ID NO:66;   (viii) the HDCR1 comprises SEQ ID NO:22, the HDCR2 comprises SEQ ID NO:23, the HDCR3 comprises SEQ ID NO:24, the LCDR1 comprises SEQ ID NO:67, the LCDR2 comprises SEQ ID NO:68, and the LCDR3 comprises SEQ ID NO:69;   (ix) the HDCR1 comprises SEQ ID NO:25, the HDCR2 comprises SEQ ID NO:26, the HDCR3 comprises SEQ ID NO:27, the LCDR1 comprises SEQ ID NO:70, the LCDR2 comprises SEQ ID NO:71, and the LCDR3 comprises SEQ ID NO:72;   (x) the HDCR1 comprises SEQ ID NO:28, the HDCR2 comprises SEQ ID NO:29, the HDCR3 comprises SEQ ID NO:30, the LCDR1 comprises SEQ ID NO:73, the LCDR2 comprises SEQ ID NO:74, and the LCDR3 comprises SEQ ID NO:75;   (xi) the HDCR1 comprises SEQ ID NO:31, the HDCR2 comprises SEQ ID NO:32, the HDCR3 comprises SEQ ID NO:33, the LCDR1 comprises SEQ ID NO:76, the LCDR2 comprises SEQ ID NO:77, and the LCDR3 comprises SEQ ID NO:78;   (xii) the HDCR1 comprises SEQ ID NO:34, the HDCR2 comprises SEQ ID NO:35, the HDCR3 comprises SEQ ID NO:36, the LCDR1 comprises SEQ ID NO:79, the LCDR2 comprises SEQ ID NO:80, and the LCDR3 comprises SEQ ID NO:81;   (xiii) the HDCR1 comprises SEQ ID NO:37, the HDCR2 comprises SEQ ID NO:38, the HDCR3 comprises SEQ ID NO:39, the LCDR1 comprises SEQ ID NO:82, the LCDR2 comprises SEQ ID NO:83, and the LCDR3 comprises SEQ ID NO:84;   (xiv) the HDCR1 comprises SEQ ID NO:40, the HDCR2 comprises SEQ ID NO:41, the HDCR3 comprises SEQ ID NO:42, the LCDR1 comprises SEQ ID NO:85, the LCDR2 comprises SEQ ID NO:86, and the LCDR3 comprises SEQ ID NO:87;   (xv) the HDCR1 comprises SEQ ID NO:43, the HDCR2 comprises SEQ ID NO:44, the HDCR3 comprises SEQ ID NO:45, the LCDR1 comprises SEQ ID NO:88, the LCDR2 comprises SEQ ID NO:89, and the LCDR3 comprises SEQ ID NO:90;   (xvi) the HDCR1 comprises SEQ ID NO:271, the HDCR2 comprises SEQ ID NO:272, the HDCR3 comprises SEQ ID NO:273, the LCDR1 comprises SEQ ID NO:283, the LCDR2 comprises SEQ ID NO:284, and the LCDR3 comprises SEQ ID NO:285;   (xvii) the HDCR1 comprises SEQ ID NO:274, the HDCR2 comprises SEQ ID NO:275, the HDCR3 comprises SEQ ID NO:276, the LCDR1 comprises SEQ ID NO:286, the LCDR2 comprises SEQ ID NO:287, and the LCDR3 comprises SEQ ID NO:288; or   (xviii) the HDCR1 comprises SEQ ID NO:277, the HDCR2 comprises SEQ ID NO:278, the HDCR3 comprises SEQ ID NO:279, the LCDR1 comprises SEQ ID NO:289, the LCDR2 comprises SEQ ID NO:290, and the LCDR3 comprises SEQ ID NO:291.   
     
     
         66 . The method of  claim 65 , wherein:
 (i) the VH comprises the amino acid sequence of SEQ ID NO:211 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:212 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (ii) the VH comprises the amino acid sequence of SEQ ID NO:213 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:214 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (iii) the VH comprises the amino acid sequence of SEQ ID NO:215 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:216 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (iv) the VH comprises the amino acid sequence of SEQ ID NO:217 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:218 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (v) the VH comprises the amino acid sequence of SEQ ID NO:219 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:220 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (vi) the VH comprises the amino acid sequence of SEQ ID NO:221 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:222 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (vii) the VH comprises the amino acid sequence of SEQ ID NO:223 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:224 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (viii) the VH comprises the amino acid sequence of SEQ ID NO:225 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:226 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (ix) the VH comprises the amino acid sequence of SEQ ID NO:227 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:228 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (x) the VH comprises the amino acid sequence of SEQ ID NO:229 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:230 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (xi) the VH comprises the amino acid sequence of SEQ ID NO:231 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:232 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (xii) the VH comprises the amino acid sequence of SEQ ID NO:233 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:234 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (xiii) the VH comprises the amino acid sequence of SEQ ID NO:235 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:236 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (xiv) the VH comprises the amino acid sequence of SEQ ID NO:237 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:238 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (xv) the VH comprises the amino acid sequence of SEQ ID NO:239 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:240 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (xvi) the VH comprises the amino acid sequence of SEQ ID NO:327 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:328 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL;   (xvii) the VH comprises the amino acid sequence of SEQ ID NO:329 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:330 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VL; or   (xviii) the VH comprises the amino acid sequence of SEQ ID NO:331 or an amino acid sequence at least 90% identical thereto wherein all differences are located in a framework region of the VH and the VL comprises the amino acid sequence of SEQ ID NO:332 or an amino acid sequence at least 90% identical thereto.   
     
     
         67 . The method of  claim 65 , wherein: 
       
         
           
                 
                 
               
                     
                   the HCDR1 comprises SEQ ID NO: 16 
                 
                     
                   (YTFTSYYMH), 
                 
                     
                     
                 
                     
                   the HCDR2 comprises SEQ ID NO: 17 
                 
                     
                   (VIGPSGASTSYAQKFQG), 
                 
                     
                     
                 
                     
                   the HCDR3 comprises SEQ ID NO: 18 
                 
                     
                   (ARDHSDYWSGIMEV), 
                 
                     
                     
                 
                     
                   the LCDR1 comprises SEQ ID NO: 61 
                 
                     
                   (RASQSVRSSYLA), 
                 
                     
                     
                 
                     
                   the LCDR2 comprises SEQ ID NO: 62 
                 
                     
                   (GASSRAT), 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   the LCDR3 comprises SEQ ID NO: 63 
                 
                     
                   (QQYFSPPWT). 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         68 . The method of  claim 67 , wherein the VH comprises the amino acid sequence shown as SEQ ID NO: 221 or an amino acid sequence exhibiting at least 90%, 95%, 97%, 98% or 99% sequence identity thereto wherein all the differences are located in a framework region of the VH, and the VL comprises the amino acid sequence shown as SEQ ID NO: 222 or an amino acid sequence exhibiting at least 90%, 95%, 97%, 98% or 99% sequence identity thereto wherein all the differences are located in the framework region of the VL. 
     
     
         69 . The method of  claim 65 , wherein the method further comprises administration of one or more additional therapeutic agent. 
     
     
         70 . The method of  claim 69 , wherein the one or more therapeutic agent is selected from: a chemotherapeutic agent, an anti-PD1 antibody, an anti-PD-L1 antibody, an anti-41BB antibody, an anti-OX40 antibody, an anti-GITR antibody, and an anti-ICOS antibody. 
     
     
         71 . The method of  claim 65 , wherein the viral infection is a CMV infection.