US2013274447A1PendingUtilityA1

Humanized antibodies against cxcr3

Assignee: TEVA BIOPHARMACEUTICALS USA INCPriority: Feb 1, 2007Filed: Apr 5, 2013Published: Oct 17, 2013
Est. expiryFeb 1, 2027(~0.5 yrs left)· nominal 20-yr term from priority
A61P 35/00A61P 35/02A61P 37/06A61P 37/00A61P 25/00A61P 29/00C07K 2317/24C07K 2317/565A61P 19/02C07K 2317/92C07K 16/2866A61P 17/06C07K 2317/56A61P 11/00A61P 1/04A61K 39/395C07K 16/28
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Claims

Abstract

Disclosed are humanized antibodies that bind specifically to the receptor CXCR3. The humanized antibodies may be antagonists and may be used to treat or diagnose conditions associated with CXCR3 function.

Claims

exact text as granted — not AI-modified
1 .- 98 . (canceled) 
     
     
         99 . A humanized antibody heavy chain variable region comprising:
 (a) a CDR-H1 comprising the amino acid sequence {N,S,Y}MAS;   (b) a CDR-H2 comprising the amino acid sequence {T,A,Y}I{S,Y}{S,G,T,Y}{G,S}{G,Y}G{F,S,Y}TYY{P,A}DS{L,Y,V}KG; and   (c) a CDR-H3 comprising the amino acid sequence {H,Y}{G,Y}{A,Y}PM{T,Y}T{V,Y}ITY{A,Y}PYYFYY.   
     
     
         100 . The humanized antibody heavy chain variable region of  claim 99 , comprising the amino acid sequence: 
       
         
           
                 
                 
               
                   EVQLLESGGGLVQPGGSLRLSCAASGFTFS{ N ,  S ,  Y } YAMS WVRQAPGKGLEWVS{ T ,  A ,  Y } 
                     
                 
                     
                 
                     I { S ,  Y }{ S ,  G ,  T ,  Y }{ G ,  S }{ G ,  Y } G { F ,  S ,  Y } TYY { P ,  A } DS { L ,  Y ,  V } KG RFTISRDNSKNTLYLQMNSL 
                 
                     
                 
                   RAEDTAVYYCAK{ H ,  Y }{ G ,  Y }{ A ,  Y } PM { T ,  Y } T { V ,  Y } ITY { A ,  Y } PYYFYY WGQGTTVTVSS. 
                 
             
                
                
                
                
                
               
            
           
         
       
     
     
         101 . A polynucleotide according to  claim 99 , wherein the polynucleotide encodes a polypeptide comprising a humanized antibody heavy chain variable region comprising:
 (a) a CDR-H1 comprising an amino acid sequence selected from the group consisting of NYAIS, YYAMS, and NYAMS;   (b) a CDR-H2 comprising an amino acid sequence selected from the group consisting of TYSSGGVYTYYRDSLKG, TIYSGGSYTFYPDSLEG, TIYSGGGYTFYLDSLKG, and TISSGGGYTYYPDSLKG; and   (c) a CDR-H3 comprising an amino acid sequence selected from the group consisting of HGAPMTTVITYAPYYF{D,Y}Y, HGAPMTTVITYAPYYFYY, HGAPMTTVITYAPYYFDY, HGAAMTTVITYAPFYFYY, HGAPMSTEITYAPYYFYY, and HSYPMTTVITYAPYYFYY.   
     
     
         102 . The polynucleotide of  claim 101 , wherein the humanized antibody heavy chain variable region comprises the amino acid sequence: 
       
         
           
                 
                 
               
                   EV{M, Q}L{V, L}ESGGGLV{K, Q}PGGSL{K, R}LSCAASGFTFSNYAMSWVRQ{T, A}P 
                     
                 
                     
                 
                   {E, G}K{R, G}LEWV{A, S}TISSGGGYTYYPDSLKGRFTISRDN{A, S}KNTL{F, Y}LQM{S, 
                 
                     
                 
                   N}SLR{S, A}EDTAVYYC{V, A}{R, K}HGAPMTTVITYAPYYF{D, Y}YWGQGTT{L, V}T 
                 
                     
                 
                   VSS. 
                 
             
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         103 . The polynucleotide of  claim 102 , wherein the humanized antibody heavy chain variable region comprises the amino acid sequence: 
       
         
           
                 
               
                   (SEQ ID NO: 11) 
                 
                   EVQLLESGGGLVQPGGSLRLSCAASGFTFS NYAMS WVRQAPKGLEWVS TI   
                 
                     
                 
                     SSGGGYTYYPDSLKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK HGA   
                 
                     
                 
                     PMTTVITYAPYYFYY WGQGTTVTVSS. 
                 
             
                
                
                
                
                
                
               
            
           
         
       
     
     
         104 . The polynucleotide of  claim 101 , wherein the polynucleotide encodes an amino acid sequence selected from the group consisting of: 
       
         
           
                 
               
                   (a) 
                 
                   EVQLLESGGGLVQPGGSLRLSCAASGFTFS NYAIS WVRQAPGKGLEWVS 
                 
                     
                 
                     TYSSGGVYTYYRDSLKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK 
                 
                     
                 
                     HGAAMTTVITYAPFYFYY WGQGTTVTVSS; 
                 
                     
                 
                   (b) 
                 
                   EVQLLESGGGLVQPGGSLRLSCAASGFTFS YYAMS WVRQAPGKGLEWVS 
                 
                     
                 
                     TIYSGGSYTFYPDSLEG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK 
                 
                     
                 
                     HGAPMSTEITYAPYYFYY WGQGTTVTVSS; 
                 
                     
                 
                   (c) 
                 
                   EVQLLESGGGLVQPGGSLRLSCAASGFTFS NYYMS WVRQAPGKGLEWVS 
                 
                     
                 
                     TIYSGGGYTFYLDSLKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK 
                 
                     
                 
                     HSYPMTTVITYAPYYFYY WGQGTTVTVSS; 
                 
                     
                 
                   (d) 
                 
                   EVQLLESGGGLVQPGGSLRLSCAASGFTFS NYAMS WVRQAPGKGLEWVS 
                 
                     
                 
                     TISSGGGYTYYPDSLKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK 
                 
                     
                 
                     HGAPMTTVITYAPYYFYY WGQGTTVTVSS; 
                 
                   and 
                 
                     
                 
                   (e) 
                 
                   EVQLLESGGGLVQPGGSLRLSCAASGFTFS NYAMS WVRQAPGKGLEWVS 
                 
                     
                 
                     TISSGGGYTYYPDSLKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK 
                 
                     
                 
                     HGAPMTTVITYAPYYFYY WGQGTTVTVSS. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         105 . A polynucleotide encoding a polypeptide comprising a humanized antibody light chain variable region comprising:
 (a) a CDR-L1 comprising the amino acid sequence: RAS{S,Q}SV{K,S}SY{M,L}{Y,A};   (b) a CDR-L2 comprising the amino acid sequence: {Y,D}{T,A}SN{L,R}A{P,T}; and   (c) a CDR-L3 comprising the amino acid sequence {Q,Y}Q{F,Y}TT{S,Y}PYT.   
     
     
         106 . The polynucleotide of  claim 105 , wherein the humanized antibody light chain variable region comprises an amino acid sequence selected from the group consisting of: 
       
         
           
                 
                 
               
                   (a) 
                     
                 
                   {E, D}{N, V}V{L, M}TQSPAFLSVTPGEKVTITC RAS { S ,  Q } SV { K ,  S } SY { M ,  L }{ Y ,  A } 
                 
                     
                 
                   WYQQKPDQAPKL{W, L}I{Y, K}{ Y ,  D }{ T ,  A } SN { L ,  R } A { P ,  T }GVPSRFSGSGSG{N, T}D{Y, 
                 
                     
                 
                   F}TFTISSLEAEDAATYYC{ Q ,  Y } Q { F ,  Y } TT { S ,  Y } PYT FGGGTKLEIKR; 
                 
                   and 
                 
                     
                 
                   (b) 
                 
                   EIVLTQSPATLSLSPGERATLSC RAS { S ,  Q } SV { K ,  S } SY { M ,  L }{ Y ,  A }WYQQKPGQAPRLLIY 
                 
                     
                 
                   { Y ,  D }{ T ,  A } SN { L ,  R } A { P ,  T }GIPARFSGSGSGTDFTLTISSLEPEDFAVYYC{ Q ,  Y } Q { F ,  Y } TT { S , 
                 
                     
                 
                     Y } PYT FGGGTKLEIKR 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         107 . A polynucleotide according to  claim 105 , wherein the polynucleotide encodes a polypeptide comprising a humanized antibody light chain variable region comprising:
 (a) a CDR-L1 comprising the amino acid sequence RASSSVKYMY;   (b) a CDR-L2 comprising the amino acid sequence YTSNLAP; and   (c) a CDR-L3 comprising an amino acid sequence selected from the group consisting of QQFTTSPYT, YQFTTSPYT, QQYTTSPYT, and QQFTTYPYT.   
     
     
         108 . The polynucleotide of  claim 107 , wherein the humanized antibody light chain variable region comprises the amino acid sequence: 
       
         
           
                 
                 
               
                   {E, D}{I, N, V}V{L, M}TQSPA{T, F, I}{L, M}S{L, A, V}{S, T}{L, P}GE{R, K}{A, V}T{L, M, I} 
                     
                 
                     
                 
                   {S, T, N}C RASSSVKYMY WYQQK{S, P}{G, D}{Q, A}{A, S}P{R, K}L{L, W}I{Y, K} YTSNLAP   
                 
                     
                 
                   G{I, V}P{A, S}RFSGSGSG{T, N}{D, S}{F, Y}{T, S}{L, F}TISS{M, L}E{A, G, P}ED{F, A}A 
                 
                     
                 
                   {V, T}YYC{ Q ,  Y } QFTT { S ,  Y } PYT FGGGTKLEIKR. 
                 
             
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         109 . The polynucleotide of  claim 107 , wherein the humanized antibody light chain variable region comprises an amino acid sequence selected from the group consisting of 
       
         
           
                 
                 
               
                   (a) 
                     
                 
                   EINVLTQSPATLSLSLGERATLSC RASSSVKYMY WYQQKSGQAPRLLIY YTSNLAP GIPA 
                 
                     
                 
                   RFSGSGSGTDFTLTISSMEAEDFAVYYC QQFTTSPYT FGGGTKLEIKR; 
                 
                     
                 
                   (b) 
                 
                   ENVLTQSPAFLSVTPGEKVTITC RASSSVKYMY WYQQKPDQAPKLWIY YTSNLAP GVPS 
                 
                     
                 
                   RFSGSGSGNDYTFTISSLEAEDAATYYC QQFTTSPYT FGGGTKLEIKR; 
                 
                     
                 
                   (c) 
                 
                   EIVLTQSPATLSLSLGERATLSC RASSSVKYMY WYQQKSGQAPRLLIY YTSNLAP GIPARF 
                 
                     
                 
                   SGSGSGTDFTLTISSMEAEDFAVYYC QQFTTSPYT FGGGTKLEIKR; 
                 
                     
                 
                   (d) 
                 
                   EIVLTQSPATLSLSPGERATLSC RASSSVKYMY WYQQKPGQAPRLLIY YTSNLAP GIPARF 
                 
                     
                 
                   SGSGSGTDFTLTISSLEPEDFAVYYC QQFTTSPYT FGGGTKLEIKR; 
                 
                     
                 
                   (e) 
                 
                   EIVLTQSPATLSLSPGERATLSC RASSSVKYMY WYQQKPGQAPRLLIY YTSNLAP GIPARF 
                 
                     
                 
                   SGSGSGTDFTLTISSLEPEDFAVYYC YQFTTSPYT FGGGTKLEIKR; 
                 
                     
                 
                   (f) 
                 
                   EIVLTQSPATLSLSPGERATLSC RASSSVKYMY WYQQKPGQAPRLLIY YTSNLAP GIPARF 
                 
                     
                 
                   SGSGSGTDFTLTISSLEPEDFAVYYC QQYTTSPYT FGGGTKLEIKR); 
                 
                     
                 
                   (g) 
                 
                   EIVLTQSPATLSLSPGERATLSC RASSSVKYMY WYQQKPGQAPRLLIY YTSNLAP GIPARF 
                 
                     
                 
                   SGSGSGTDFTLTISSLEPEDFAVYYC QQFTTYPYT FGGGTKLEIKR; 
                 
                   and 
                 
                     
                 
                   (h) 
                 
                   ENVLTQSPAFLSVTPGEKVTITC RASSSVKYMY WYQQKPDQAPKLWIY YTSNLAP GVPS 
                 
                     
                 
                   RFSGSGSGNDYTFTISSLEAEDAATYYC QQFTTSPYT FGGGTKLEIKR. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         110 . A polynucleotide encoding a polypeptide comprising:
 (a) a humanized antibody heavy chain variable region comprising:
 (1) a CDR-H1 comprising the amino acid sequence NYMAS; 
 (2) a CDR-H2 comprising the amino acid sequence TISSGGGYTYYPDSLKG; and 
 (3) a CDR-H3 comprising an amino acid sequence selected from the group consisting of HGAPMTTVITYAPYYF{D,Y}Y), HGAPMTTVITYAPYYFYY, and HGAPMTTVITYAPYYFDY; and 
   (b) a humanized antibody light chain variable region comprising:
 (1) a CDR-L1 comprising the amino acid sequence RASSSVKYMY; 
 (2) a CDR-L2 comprising the amino acid sequence YTSNLAP; and 
 (3) a CDR-L3 comprising the amino acid sequence QQFTTSPYT, YQFTTSPYT, and QQYTTSPYT. 
   
     
     
         111 . The polynucleotide of  claim 110 , wherein:
 (a) the CDR-H1 comprises the amino acid sequence NYMAS;   (b) the CDR-H2 comprises the amino acid sequence TISSGGGYTYYPDSLKG;   (c) the CDR-H3 comprises the amino acid sequence HGAPMTTVITYAPYYF{D,Y}Y;   (d) the CDR-L1 comprises the amino acid sequence RASSSVKYMY;   (e) the CDR-L2 comprises the amino acid sequence YTSNLAP; and   (f) the CDR-L3 comprises the amino acid sequence QQFTTSPYT.   
     
     
         112 . A recombinant polynucleotide comprising a promoter sequence operably linked to the polynucleotide of  claim 110 . 
     
     
         113 . An isolated cell transformed with the polynucleotide of  claim 112 . 
     
     
         114 . A polynucleotide according to  claim 110 , wherein the polypeptide comprises:
 (a) a humanized heavy chain variable region comprising the amino acid sequence:   
       
         
           
                 
               
                   EVQLLESGGGLVQPGGSLRLSCAASGFTFS NYAMS WVRQAPGKGLEWVS T   
                 
                     
                 
                     ISSGGGYTYYPDSLKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK HG   
                 
                     
                 
                     APMTTVITYAPYYFYY WGQGTTVTVSS; 
                 
             
                
                
                
                
                
               
            
           
         
       
       and
 (b) a humanized light chain variable region comprising the amino acid sequence 
 
       
         
           
                 
                 
               
                   EIVLTQSPATLSLSLGERATLSC RASSSVKYMY WYQQKSGQAPRLLIY YTSNLAP GIPARF 
                     
                 
                     
                 
                   SGSGSGTDFTLTISSMEAEDFAVYYC QQFTTSPYT FGGGTKLEIKR. 
                 
             
                
                
                
               
            
           
         
       
     
     
         115 . A polynucleotide according to  claim 110 , wherein the polypeptide comprises:
 (a) a humanized heavy chain variable region comprising the amino acid sequence:   
       
         
           
                 
               
                   EVQLLESGGGLVQPGGSLRLSCAASGFTFS NYAMS WVRQAPGKGLEWVS T   
                 
                     
                 
                     ISSGGGYTYYPDSLKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK HG   
                 
                     
                 
                     APMTTVITYAPYYFYY WGQGTTVTVSS; 
                 
             
                
                
                
                
                
               
            
           
         
       
       and
 (b) a humanized light chain variable region comprising the amino acid sequence: 
 
       
         
           
                 
               
                   ENVLTQSPAFLSVTPGEKVTITC RASSSVKYMY WYQQKPDQAPKLWIY YT   
                 
                     
                 
                     SNLAP GVPSRFSGSGSGNDYTFTISSLEAEDAATYYC QQFTTSPYT FGGG 
                 
                     
                 
                   TKLEIKR. 
                 
             
                
                
                
                
                
               
            
           
         
       
     
     
         116 . A polynucleotide according to  claim 110 , wherein the polypeptide comprises:
 (a) a humanized heavy chain variable region comprising the amino acid sequence:   
       
         
           
                 
               
                   EVQLLESGGGLVQPGGSLRLSCAASGFTFS NYAMS WVRQAPGKGLEWVS T   
                 
                     
                 
                     ISSGGGYTYYPDSLKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK HG   
                 
                     
                 
                     APMTTVITYAPYYFYY WGQGTTVTVSS; 
                 
             
                
                
                
                
                
               
            
           
         
       
       and
 (b) a humanized light chain variable region comprising the amino acid sequence 
 
       
         
           
                 
                 
               
                   EIVLTQSPATLSLSPGERATLSC RASSSVKYMY WYQQKPGQAPRLLIY YTSNLAP GIPARF 
                     
                 
                     
                 
                   SGSGSGTDFTLTISSLEPEDFAVYYC QQFTTSPYT FGGGTKLEIKR. 
                 
             
                
                
                
               
            
           
         
       
     
     
         117 . A polynucleotide according to  claim 110 , wherein the polypeptide comprises:
 (a) a humanized heavy chain variable region comprising the amino acid sequence:   
       
         
           
                 
               
                   EVQLLESGGGLVQPGGSLRLSCAASGFTFS NYAMS WVRQAPGKGLEWVS T   
                 
                     
                 
                     ISSGGGYTYYPDSLKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK HG   
                 
                     
                 
                     APMTTVITYAPYYFYY WGQGTTVTVSS; 
                 
             
                
                
                
                
                
               
            
           
         
       
       and
 (b) a humanized light chain variable region comprising the amino acid sequence 
 
       
         
           
                 
                 
               
                   EIVLTQSPATLSLSPGERATLSC RASSSVKYMY WYQQKPGQAPRLLIY YTSNLAP GIPARF 
                     
                 
                     
                 
                   SGSGSGTDFTLTISSLEPEDFAVYYC YQFTTSPYT FGGGTKLEIKR. 
                 
             
                
                
                
               
            
           
         
       
     
     
         118 . A polynucleotide according to  claim 110 , wherein the polypeptide comprises:
 (a) a humanized heavy chain variable region comprising the amino acid sequence:   
       
         
           
                 
               
                   EVQLLESGGGLVQPGGSLRLSCAASGFTFS NYAMS WVRQAPGKGLEWVS T   
                 
                     
                 
                     ISSGGGYTYYPDSLKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK HG   
                 
                     
                 
                     APMTTVITYAPYYFYY WGQGTTVTVSS; 
                 
             
                
                
                
                
                
               
            
           
         
       
       and
 (b) a humanized light chain variable region comprising the amino acid sequence 
 
       
         
           
                 
                 
               
                   EIVLTQSPATLSLSPGERATLSC RASSSVKYMY WYQQKPGQAPRLLIY YTSNLAP GIPARF 
                     
                 
                     
                 
                   SGSGSGTDFTLTISSLEPEDFAVYYC QQYTTSPYT FGGGTKLEIKR. 
                 
             
                
                
                
               
            
           
         
       
     
     
         119 . A polynucleotide according to  claim 110 , wherein the polypeptide comprises:
 (a) a humanized heavy chain variable region comprising the amino acid sequence:   
       
         
           
                 
               
                   EVQLLESGGGLVQPGGSLRLSCAASGFTFS NYAMS WVRQAPGKGLEWVS T   
                 
                     
                 
                     ISSGGGYTYYPDSLKG RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK HG   
                 
                     
                 
                     APMTTVITYAPYYFYY WGQGTTVTVSS; 
                 
             
                
                
                
                
                
               
            
           
         
       
       and
 (b) a humanized light chain variable region comprising the amino acid sequence 
 
       
         
           
                 
                 
               
                   EIVLTQSPATLSLSPGERATLSC RASSSVKYMY WYQQKPGQAPRLLIY YTSNLAP GIPARF 
                     
                 
                     
                 
                   SGSGSGTDFTLTISSLEPEDFAVYYC QQFTTYPYT FGGGTKLEIKR.

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