Complement Pathway Inhibitors Binding To C5 And C5A Without Preventing The Formation Of C5B

Abstract

The invention relates to inhibitors that bind to C5 and C5a, but which do not prevent the activation of C5 and do not prevent formation of or inhibit the activity of C5b. One example of such an inhibitor molecule is the monoclonal antibody designated MAb137-26, which binds to a shared epitope of human C5 and C5a. These inhibitors may be used to inhibit the activity of C5a in treating diseases and conditions mediated by excessive or uncontrolled production of C5a. The inhibitor molecules are also useful for diagnostic detection of the presence/absence or amount of C5 or C5a.

1 - 17 . (canceled) 
     
     
         18 . An isolated antibody or an antigen-binding fragment thereof that binds to the same epitope of human C5 as the monoclonal antibody 137-26 produced from the hybridoma deposited with the ATCC and designated PTA-3650. 
     
     
         19 . The antibody or antigen binding fragment thereof of  claim 18 , wherein the antibody or antigen-binding fragment binds to human C5 and C5a, but does not prevent the activation of C5 and does not prevent formation of or inhibit the activity of C5b. 
     
     
         20 . The antibody or antigen binding fragment thereof of  claim 18 , wherein the antibody or antigen-binding fragment binds an epitope having the amino acid sequence of EQRAARISLGPR. 
     
     
         21 . The antibody or antigen binding fragment thereof of  claim 18 , wherein the antibody or the antigen-binding fragment thereof inhibits human neutrophil activation with at least equal potency as the monoclonal antibody 137-26 produced from the hybridoma deposited with the ATCC and designated PTA-3650. 
     
     
         22 . The antibody or antigen binding fragment of  claim 21 , wherein the inhibition of human neutrophil activation is determined by measuring the expression of CD11b or the oxidative burst in neutrophils, induced by opsonized  Escherichia coli  in lepirudin-treated whole human blood. 
     
     
         23 . The antibody or antigen binding fragment of  claim 19 , wherein the antibody or antigen-binding fragment binds to free human C5a with equal or better affinity than to human C5. 
     
     
         24 . The antibody or antigen binding fragment of  claim 19 , wherein the antibody or antigen-binding fragment inhibits the binding of human C5a to human C5a receptor. 
     
     
         25 . The antibody or antigen binding fragment of  claim 18 , wherein the antibody is a monoclonal antibody. 
     
     
         26 . The antibody or antigen binding fragment thereof of  claim 18 , wherein the fragment is selected from the group consisting of Fab, F(ab′) 2 , Fv, and single chain Fv. 
     
     
         27 . The antibody or antigen binding fragment thereof of  claim 18 , wherein the antibody is a chimeric, deimmunized, humanized or a human antibody. 
     
     
         28 . The antibody or antigen binding fragment thereof of  claim 18 , wherein the antibody or antigen binding fragment comprises a polymer that increases the half life of circulation of the antibody. 
     
     
         29 . The antibody or antigen binding fragment thereof of  claim 18 , wherein the polymer is polyethylene glycol having an average molecular weight between (i) 1,000 and 40,000; (ii) 2,000 and 20,000; or (iii) 3,000 and 12,000. 
     
     
         30 . A pharmaceutical composition comprising the antibody or fragment thereof according to  claim 18 , and a pharmacologically acceptable carrier, excipient, stabilizer, or diluent. 
     
     
         31 . A method of inhibiting the activity of human C5a comprising contacting human C5a with an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment binds to the same epitope on human C5 and human C5a as the monoclonal antibody 137-26 produced by the hybridoma deposited with the ATCC and designated PTA-3650. 
     
     
         32 . A method of treating a complement mediated disease or condition comprising administering to a subject in need thereof an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment binds to the same epitope on human C5 and human C5a as the monoclonal antibody 137-26 produced by the hybridoma deposited with the ATCC and designated PTA-3650. 
     
     
         33 . A method for detecting human C5 or human C5a comprising binding an antibody or antigen binding fragment thereof to the human C5 or human C5a, wherein the antibody or antigen binding fragment binds to the same epitope on human C5 and human C5a as the monoclonal antibody 137-26 produced by the hybridoma deposited with the ATCC and designated PTA-3650. 
     
     
         34 . The method of  claim 33 , further comprising quantitating the amount of human C5 or human C5a. 
     
     
         35 . The method of  claim 31 , wherein the antibody or antigen-binding fragment binds an epitope having the amino acid sequence of EQRAARISLGPR. 
     
     
         36 . The method of  claim 31 , wherein the antibody or antigen binding fragment binds to free human C5a with equal or better affinity than to human C5. 
     
     
         37 . The method of  claim 31 , wherein the antibody or antigen binding fragment inhibits the binding of human C5a to human C5a receptor. 
     
     
         38 . The method of  claim 31 , wherein the antibody is a monoclonal antibody. 
     
     
         39 . The method of  claim 31 , wherein the antibody is chimeric, deimmunized, or humanized, or a human antibody. 
     
     
         40 . The method of  claim 31 , wherein the antigen binding fragment is a Fab, F(ab′)2, Fv, or single chain Fv. 
     
     
         41 . The method of  claim 31 , wherein the antibody or antigen binding fragment comprises a polymer that increases the half life of circulation of the antibody. 
     
     
         42 . The method of  claim 41 , wherein the polymer is polyethylene glycol having an average molecular weight between (i) 1,000 and 40,000; (ii) 2,000 and 20,000; or (iii) 3,000 and 12,000. 
     
     
         43 . The method of  claim 32 , wherein the antibody or antigen binding fragment is in a composition comprising a pharmacologically acceptable carrier, excipient, stabilizer, or diluent. 
     
     
         44 . The method of  claim 32 , wherein the antibody or antigen binding fragment is administered by intravenous, intraperitoneal, intradermal, intramuscular, subcutaneous, intranasal, intratracheal, intraspinal, or intracranial injection, by intravenous bolus injection, by infusion, or orally. 
     
     
         45 . The method of  claim 32 , wherein the antibody or antigen binding fragment is administered ex vivo. 
     
     
         46 . The method of  claim 32 , wherein the disease or condition is complement-mediated inflammation, complement-mediated tissue damage, bacterial sepsis, chronic immune complex disease, psoriasis, septic shock, myocardial ischemia/reperfusion injury, intestinal ischemia/reperfusion injury, graft rejection, organ failure, nephritis, autoimmune diseases, or rheumatoid arthritis. 
     
     
         47 . The method of  claim 33 , wherein the inhibition of C5a is determined in vitro.