Tlr3 binding agents

Abstract

The present invention relates to antibodies (e.g. monoclonal antibodies), antibody fragments, and derivatives thereof that specifically bind TLR3, and that optionally further modulate, e.g. inhibit, signaling. The invention also relates to cells producing such antibodies; methods of making such antibodies; fragments, variants, and derivatives of the antibodies; pharmaceutical compositions comprising the same; methods of using the antibodies to diagnose, treat or prevent diseases, e.g. autoimmune diseases, inflammatory diseases and the like.

What is claimed is: 
     
         1 . A method for treating or preventing a disease selected from the group consisting of autoimmunity, inflammation, allergy, asthma, infection, cirrhosis and sepsis, said method comprising administering to a patient in need thereof a therapeutically effective amount of an antibody that specifically binds a human Toll-like receptor 3 (TLR3) polypeptide, wherein said antibody inhibits signaling by said human TLR3 polypeptide without blocking binding of a double-stranded ribonucleic acid (dsRNA) TLR3 ligand to said human TLR3 polypeptide. 
     
     
         2 . A method for treating or preventing a disease selected from the group consisting of autoimmunity, inflammation, allergy, asthma, infection, cirrhosis and sepsis, said method comprising administering to a patient in need thereof a therapeutically effective amount of an antibody that specifically binds a human Toll-like receptor 3 (TLR3) polypeptide, wherein said antibody specifically binds to said human TLR3 polypeptide under acidic conditions with a sub-nanomolar K D  for its bivalent binding affinity. 
     
     
         3 . A method for treating or preventing a disease selected from the group consisting of autoimmunity, inflammation, allergy, asthma, infection, cirrhosis and sepsis, said method comprising administering to a patient in need thereof a therapeutically effective amount of an antibody that specifically binds a human Toll-like receptor 3 (TLR3) polypeptide, wherein said antibody has respectively a VH and VL region of SEQ ID NO: 2 and 3 (31C3). 
     
     
         4 . The method of  claim 1 , further comprising the step of administering to the patient an appropriate additional therapeutic agent selected from the group consisting of an immunomodulatory agent, a corticosteroid, an immunosuppressant, an antibiotic, an antiviral and an anti-inflammatory agent. 
     
     
         5 . The method of  claim 2 , further comprising the step of administering to the patient an appropriate additional therapeutic agent selected from the group consisting of an immunomodulatory agent, a corticosteroid, an immunosuppressant, an antibiotic, an antiviral and an anti-inflammatory agent. 
     
     
         6 . The method of  claim 3 , further comprising the step of administering to the patient an appropriate additional therapeutic agent selected from the group consisting of an immunomodulatory agent, a corticosteroid, an immunosuppressant, an antibiotic, an antiviral and an anti-inflammatory agent. 
     
     
         7 . A method for treating or preventing a cancer, comprising administering to a patient in need thereof a therapeutically effective amount of an antibody that specifically binds a human Toll-like receptor 3 (TLR3) polypeptide, wherein said antibody inhibits signaling by said human TLR3 polypeptide without blocking binding of a double-stranded ribonucleic acid (dsRNA) TLR3 ligand to said human TLR3 polypeptide, and wherein said antibody is conjugated or covalently bound to a toxic moiety. 
     
     
         8 . A method for treating or preventing a cancer, comprising administering to a patient in need thereof a therapeutically effective amount of an antibody that specifically binds a human Toll-like receptor 3 (TLR3) polypeptide, wherein said antibody specifically binds to said human TLR3 polypeptide under acidic conditions with a sub-nanomolar K D  for its bivalent binding affinity, and wherein said antibody is conjugated or covalently bound to a toxic moiety. 
     
     
         9 . A method for treating or preventing a cancer, comprising administering to a patient in need thereof a therapeutically effective amount of an antibody that specifically binds a human Toll-like receptor 3 (TLR3) polypeptide, wherein said antibody has respectively a VH and VL region of SEQ ID NO: 2 and 3 (31C3), and wherein said antibody is conjugated or covalently bound to a toxic moiety. 
     
     
         10 . The method of  claim 7 , wherein said antibody is capable of being internalized by a TLR3-expressing cell. 
     
     
         11 . The method of  claim 8 , wherein said antibody is capable of being internalized by a TLR3-expressing cell. 
     
     
         12 . The method of  claim 9 , wherein said antibody is capable of being internalized by a TLR3-expressing cell. 
     
     
         13 . A method for treating or preventing a disease wherein the inhibition of TLR3 signaling pathway is desirable, said method comprising administering a therapeutically effective amount of an antibody to a patient in need thereof, wherein the antibody specifically binds a human Toll-like receptor 3 (TLR3) polypeptide, and wherein said antibody is selected from the group consisting of:
 (a) an antibody having respectively a VH and VL region of SEQ ID NO: 34 and 35 (34A3),   (b) an antibody having respectively a VH and VL region of SEQ ID NO: 10 and 11 (29H3),   (c) an antibody having respectively a VH and VL region of SEQ ID NO: 18 and 19 (28F11), and   (d) an antibody having respectively a VH and VL region of SEQ ID NO: 26 and 27 (23C8).   
     
     
         14 . The method of  claim 13 , wherein said disease is selected from the group consisting of autoimmunity, inflammation, allergy, asthma, infection, cirrhosis, sepsis, diabetes, and viral infections. 
     
     
         15 . A method for treating or preventing a disease wherein the inhibition of TLR3 signaling pathway is desirable, said method comprising administering a therapeutically effective amount of an antibody to a patient in need thereof, wherein said antibody competes for binding to a TLR3 polypeptide with any one or any combination of monoclonal antibodies 31C3, 29H3, 23C8, 28F11, and 34A3. 
     
     
         16 . The method of  claim 15 , wherein said disease is selected from the group consisting of autoimmunity, inflammation, allergy, asthma, infection, cirrhosis, sepsis, diabetes, and viral infections. 
     
     
         17 . A method for treating or preventing a disease wherein the inhibition of TLR3 signaling pathway is desirable, said method comprising administering a therapeutically effective amount of an antibody to a patient in need thereof, wherein said antibody is specific for an epitope in the human Toll-like receptor 3 (TLR3) polypeptide that does not undergo substantial change in electrostatic potential or undergoes less change than a region of positive electrostatic potential when neutral conditions are acidified such that the binding affinity of said antibody remains substantially unchanged. 
     
     
         18 . The method of  claim 17 , wherein said disease is selected from the group consisting of autoimmunity, inflammation, allergy, asthma, infection, cirrhosis, sepsis, diabetes, and viral infections. 
     
     
         19 . A method for treating or preventing a disease wherein the inhibition of TLR3 signaling pathway is desirable, said method comprising administering a therapeutically effective amount of an antibody to a patient in need thereof, wherein said antibody specifically binds to the same human Toll-like receptor 3 (TLR3) epitope as any one or any combination of monoclonal antibodies 31C3, 29H3, 23C8, 28F11 or 34A3. 
     
     
         20 . The method of  claim 19 , wherein said disease is selected from the group consisting of autoimmunity, inflammation, allergy, asthma, infection, cirrhosis, sepsis, diabetes, and viral infections.