US2010303726A1PendingUtilityA1

Humanized collagen antibodies and related methods

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Assignee: CELLMATRIXPriority: Nov 26, 2001Filed: Jun 10, 2010Published: Dec 2, 2010
Est. expiryNov 26, 2021(expired)· nominal 20-yr term from priority
Inventors:Jeffry D. WatkinsWilliam D. HuseYing TangDaniel BroekPeter Brooks
A61K 47/6851A61P 9/00C07K 2317/24A61K 2039/505C07K 2317/55A61P 35/00A61K 47/6843C07K 16/30A61P 35/04C07K 2317/565
59
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Claims

Abstract

The invention provides a grafted antibody, or functional fragment thereof, comprising one or more complementarity determining regions (CDRs) having at least one amino acid substitution in one or more CDRs of a heavy chain CDR, where the grafted antibody or functional fragment thereof has specific binding activity for a cryptic collagen epitope. The invention also provides methods of using an antibody having specific binding activity for a cryptic collagen epitope, including methods of inhibiting angiogenesis, tumor growth, and metastasis.

Claims

exact text as granted — not AI-modified
1 . An antibody, or antigen-binding fragment thereof, having a heavy chain variable region and a light chain variable region in which one or more complementarity determining regions (CDRs) differ in amino acid sequence from the corresponding CDRs of monoclonal antibody HUI77, and having higher binding affinity for denatured collagen type I or IV over native collagen type I or IV,
 said antibody, or antigen-binding fragment thereof, comprising:   a heavy chain CDR1 referenced as SEQ ID NO: 38 or SEQ ID NO: 38 having one or more substitutions therein;   a heavy chain CDR2 referenced as SEQ ID NO: 40 or SEQ ID NO: 40 having one or more substitutions therein;   a heavy chain CDR3 referenced as SEQ ID NO: 42 or SEQ ID NO: 42 having one or more substitutions therein;   a light chain CDR1 referenced as SEQ ID NO: 32 or SEQ ID NO: 32 having one or more substitutions therein;   a light chain CDR2 referenced as SEQ ID NO: 34 or SEQ ID NO: 34 having one or more substitutions therein; and   a light chain CDR3 referenced as SEQ ID NO: 36 or SEQ ID NO: 36 having one or more substitutions therein.   
     
     
         2 . An antigen-binding fragment of  claim 1 , that is a Fv, a Fab, a F(ab′) 2  or a scFv fragment. 
     
     
         3 . A nucleic acid encoding the antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         4 . The antibody, or antigen-binding fragment thereof, of  claim 1 , further comprising a therapeutic moiety. 
     
     
         5 . The antibody, or antigen-binding fragment thereof, of  claim 1 , further comprising a detectable moiety. 
     
     
         6 . The antibody or antigen-binding fragment thereof, of  claim 1 , wherein said heavy chain CDRs are grafted into a VHIII/JH6 heavy chain variable region framework referenced as SEQ ID NO: 8. 
     
     
         7 . The antibody or antigen-binding fragment thereof, of  claim 1 , comprising two substitutions in one or more of the CDRs. 
     
     
         8 . The antibody or antigen-binding fragment thereof, of  claim 1 , comprising three substitutions in one or more of the CDRs. 
     
     
         9 . The antibody or antigen-binding fragment thereof, of  claim 1 , comprising four substitutions in one or more of the CDRs. 
     
     
         10 . The antibody or antigen-binding fragment thereof, of  claim 1 , comprising five or more substitutions in one or more of the CDRs. 
     
     
         11 . A method of targeting angiogenic vasculature, inhibiting angiogenesis, targeting a tumor or inhibiting tumor growth, comprising administering an antibody, or antigen-binding fragment thereof, of  claim 1  to a patient in need thereof. 
     
     
         12 . The method of  claim 11 , wherein said antibody, or antigen-binding fragment thereof, further comprises a therapeutic moiety. 
     
     
         13 . The method of  claim 11 , wherein said antibody, or antigen-binding fragment thereof, further comprises a detectable moiety. 
     
     
         14 . A method of detecting angiogenic vasculature, comprising contacting angiogenic vasculature with an antibody, or antigen-binding fragment thereof, of  claim 1 . 
     
     
         15 . The method of  claim 14 , wherein said antibody, or antigen-binding fragment thereof, further comprises a detectable moiety. 
     
     
         16 . The method of  claim 14 , wherein said antibody, or antigen-binding fragment thereof, further comprises a therapeutic moiety. 
     
     
         17 . A grafted antibody, or antigen-binding fragment thereof, having a heavy chain variable region and a light chain variable region in which one or more complementarity determining regions (CDRs) differ in amino acid sequence from the corresponding CDRs of monoclonal antibody HUI77, and having higher binding affinity for denatured collagen type I or IV over native collagen type I or IV,
 said antibody, or antigen-binding fragment thereof, comprising:   a heavy chain CDR1 referenced as SEQ ID NO: 38 or SEQ ID NO: 38 having one or more substitutions therein;   a heavy chain CDR2 referenced as SEQ ID NO: 40 or SEQ ID NO: 40 having one or more substitutions therein;   a heavy chain CDR3 referenced as SEQ ID NO: 42 or SEQ ID NO: 42 having one or more substitutions therein;   a light chain CDR1 referenced as SEQ ID NO: 32 or SEQ ID NO: 32 having one or more substitutions therein;   a light chain CDR2 referenced as SEQ ID NO: 34 or SEQ ID NO: 34 having one or more substitutions therein; and   a light chain CDR3 referenced as SEQ ID NO: 36 or SEQ ID NO: 36 having one or more substitutions therein.   
     
     
         18 . The grafted antibody or antigen-binding fragment thereof, of  claim 17 , wherein said heavy chain CDRs are grafted into a VHIII/JH6 heavy chain variable region. 
     
     
         19 . The grafted antibody, or antigen-binding fragment thereof, of  claim 17 , further comprising a therapeutic moiety. 
     
     
         20 . The grafted antibody, or antigen-binding fragment thereof, of  claim 17 , further comprising a detectable moiety. 
     
     
         21 . The antigen-binding fragment of  claim 17 , that is a Fv, a Fab, a F(ab′) 2  or a scFv fragment. 
     
     
         22 . A nucleic acid encoding the grafted antibody, or antigen-binding fragment thereof, of  claim 17 . 
     
     
         23 . The grafted antibody or antigen-binding fragment thereof, of  claim 17 , comprising two substitutions in one or more of the CDRs. 
     
     
         24 . The grafted antibody or antigen-binding fragment thereof, of  claim 17 , comprising three substitutions in one or more of the CDRs. 
     
     
         25 . The grafted antibody or antigen-binding fragment thereof, of  claim 17 , comprising four substitutions in one or more of the CDRs. 
     
     
         26 . The grafted antibody or antigen-binding fragment thereof, of  claim 17 , comprising five or more substitutions in one or more of the CDRs. 
     
     
         27 . A method of targeting angiogenic vasculature, inhibiting angiogenesis, targeting a tumor or inhibiting tumor growth, comprising administering a grafted antibody, or antigen-binding fragment thereof, of  claim 17 . 
     
     
         28 . The method of  claim 27 , wherein said grafted antibody, or antigen-binding fragment thereof, further comprises a therapeutic moiety. 
     
     
         29 . The method of  claim 27 , wherein said grafted antibody, or antigen-binding fragment thereof, further comprises a detectable moiety. 
     
     
         30 . A method of detecting angiogenic vasculature, comprising contacting angiogenic vasculature with a grafted antibody, or antigen-binding fragment thereof, of  claim 17 . 
     
     
         31 . The method of  claim 30 , wherein said grafted antibody, or antigen-binding fragment thereof, further comprises a detectable moiety. 
     
     
         32 . The method of  claim 30 , wherein said grafted antibody, or antigen-binding fragment thereof, further comprises a therapeutic moiety.

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