Process for inhibiting complement activation via the alternative pathway

Abstract

A process of inhibiting activation of complement via the alternative pathway, including inhibiting the formation of complement activation products via the alternative pathway, is provided.

What is claimed is:  
     
         1 . A process of inhibiting alternative complement activation comprising inhibiting properdin-induced stabilization of C3 convertase.  
     
     
         2 . The process of  claim 1  wherein the properdin-induced stabilization of C3 convertase is inhibited by inhibiting the binding of properdin to C3b.  
     
     
         3 . The process of  claim 2  wherein the binding of properdin of C3b is inhibited by exposing properdin to an effective amount of an anti-properdin antibody.  
     
     
         4 . The process of  claim 3  wherein the C3b is in the form of C3bBb.  
     
     
         5 . The process of  claim 3  wherein the anti-properdin antibody is a monoclonal antibody.  
     
     
         6 . The process of  claim 3  wherein the C3b is located in the plasma or interstitial fluid of a subject.  
     
     
         7 . The process of  claim 6  wherein the subject is a human subject.  
     
     
         8 . The process of  claim 7  wherein the human subject's complement has been activated.  
     
     
         9 . The process of  claim 8  wherein complement activation is via an acute pathological injury such as myocardial infarction, acute respiratory distress syndrome, burn injury, stroke, pancreatitis, cardiopulmonary bypass, or ischemia/reperfusion injury.  
     
     
         10 . The process of  claim 8  wherein complement activation contributes to a chronic condition such as multiple sclerosis, rheumatoid arthritis, myasthenia gravis or Alzheimer's disease.  
     
     
         11 . The process of  claim 6  wherein the anti-properdin antibody is administered into the plasma or interstitial fluid of the subject.  
     
     
         12 . A process of inhibiting the adverse effects of alternative complement pathway activation in a subject comprising administering to the subject an amount of an anti-properdin agent effective to selectively inhibit formation of an alternative complement pathway activation product.  
     
     
         13 . The process of  claim 12  wherein of the alternative complement pathway activation product is MAC.  
     
     
         14 . The process of  claim 12  wherein the alternative complement pathway activation product is C3a or C5a.  
     
     
         15 . The process of  claim 12  wherein the anti-properdin agent is an anti-properdin antibody.  
     
     
         16 . The process of  claim 12  wherein the anti-properdin agent is an antigen-binding fragment of an anti-properdin antibody.  
     
     
         17 . The process of  claim 12  wherein the anti-properdin agent is a properdin-derived peptide.  
     
     
         18 . The process of  claim 12  wherein the anti-properdin agent lacks the ability to activate Fcγ receptors.  
     
     
         19 . A process for inhibiting the adverse effects of classical complement pathway activation in a subject in which the classical complement pathway is initiated comprising administering to the subject an amount of an anti-properdin agent effective to selectively inhibit formation of an alternative complement pathway activation product.  
     
     
         20 . The process of  claim 19  wherein the alternative complement pathway activation product is MAC.  
     
     
         21 . The process of  claim 19  wherein the alternative complement pathway activation product is C3a or C5a.  
     
     
         22 . The process of  claim 19  wherein the anti-properdin agent is an anti-properdin antibody.  
     
     
         23 . The process of  claim 19  wherein the anti-properdin agent is an antigen-binding fragment of an anti-properdin antibody.  
     
     
         24 . The process of  claim 19  wherein the anti-properdin agent is a properdin-derived peptide.  
     
     
         25 . The process of  claim 19  wherein the anti-properdin agent lacks the ability to activate Fcγ receptors.  
     
     
         26 . A process for inhibiting the adverse effects of classical complement pathway activation in a subject in which the classical complement pathway is initiated comprising administering to the subject an amount of an agent that inhibits alternative pathway C3 convertase effective to selectively inhibit formation of an alternative complement pathway activation product.  
     
     
         27 . The process of  claim 26  wherein the alternative complement pathway activation product is MAC.  
     
     
         28 . The process of  claim 26  wherein the alternative complement pathway activation product is C3a or C5a.  
     
     
         29 . The process of  claim 26  wherein the agent is an anti-properdin antibody.  
     
     
         30 . The process of  claim 26  wherein the agent is an antigen-binding fragment of an anti-properdin antibody.  
     
     
         31 . The process of  claim 26  wherein the agent is a properdin-derived peptide.  
     
     
         32 . The process of  claim 26  wherein the agent lacks the ability to activate Fcγ receptors.  
     
     
         33 . A process for performing a medical procedure on a subject comprising: 
 (a) passing circulating blood from a blood vessel of the subject, through a conduit, and back to a blood vessel of the subject, the conduit having a luminal surface comprising a material capable of causing at least one of complement activation, platelet activation, leukocyte activation, or platelet-leukocyte adhesion in the subject's blood; and    (b) introducing an anti-properdin agent into the subject's bloodstream in an amount effective to reduce at least one of complement activation, platelet activation, leukocyte activation, or platelet-leukocyte adhesion resulting from passage of the circulating blood through the conduit, wherein step (a) occurs before and/or during and/or after step (b).    
     
     
         34 . The process of  claim 33  wherein the anti-properdin agent reduces the alternative pathway-dependent conversion of complement component C3 into complement components C3a and C3b.  
     
     
         35 . The process of  claim 33  wherein the anti-properdin agent reduces the alternative pathway-dependent formation of C5b-C9.  
     
     
         36 . The process of  claim 33  wherein the anti-properdin agent reduces the alternative pathway-dependent leukocyte activation.  
     
     
         37 . The process of  claim 33  wherein the anti-properdin agent specifically binds to properdin and inhibits alternative pathway C3 convertase.  
     
     
         38 . The process of  claim 33  wherein the medical procedure is an extracorporeal circulation procedure.  
     
     
         39 . The process of  claim 38  wherein the extracorporeal circulation procedure is a cardiopulmonary bypass procedure.  
     
     
         40 . The process of  claim 33  wherein the anti-properdin agent is an anti-properdin antibody.  
     
     
         41 . The process of  claim 33  wherein the anti-properdin agent is an antigen-binding fragment of an anti-properdin antibody.  
     
     
         42 . The process of  claim 33  wherein the anti-properdin agent is a properdin-derived peptide.  
     
     
         43 . The process of  claim 33  wherein the anti-properdin agent lacks the ability to activate Fcγ receptors.  
     
     
         44 . An article of manufacture comprising packaging material and a pharmaceutical agent contained within the packaging material, wherein: 
 (a) the pharmaceutical agent comprises an anti-properdin agent, the anti-properdin agent being effective for reducing at least one of complement activation, platelet activation, leukocyte activation, or platelet adhesion caused by passage of circulating blood from a blood vessel of a subject, through a conduit, and back to a blood vessel of the subject, the conduit having a luminal surface comprising a material capable of causing at least one of complement activation, platelet activation, leukocyte activation, or platelet-leukocyte adhesion in the subject's blood; and    (b) the packaging material comprises a label which indicates that the pharmaceutical agent is for use in association with an extracorporeal circulation procedure.    
     
     
         45 . The article of manufacture of  claim 44  wherein the label indicates that the pharmaceutical agent is for use in association with a cardiopulmonary bypass procedure.  
     
     
         46 . Use of an anti-properdin agent in the preparation of a medicament for selectively inhibiting formation of an alternative complement pathway activation product in a subject.  
     
     
         47 . The use of  claim 46  wherein the alternative complement pathway activation product is MAC.  
     
     
         48 . The use of  claim 46  wherein the alternative complement pathway activation product is C3a or C5a.  
     
     
         49 . The use of  claim 46  wherein the anti-properdin agent is an anti-properdin antibody.  
     
     
         50 . The use of  claim 46  wherein the anti-properdin agent is an antigen-binding fragment of an anti-properdin antibody.  
     
     
         51 . The use of  claim 46  wherein the anti-properdin agent is a properdin-derived peptide.  
     
     
         52 . The use of  claim 46  wherein the anti-properdin agent lacks the ability to activate Fcγ receptors.  
     
     
         53 . Use of an anti-properdin agent in the preparation of a medicament for selectively inhibiting formation of an alternative complement pathway activation product in a subject in which the classical complement pathway is initiated.  
     
     
         54 . The use of  claim 53  wherein the alternative complement pathway activation product is MAC.  
     
     
         55 . The use of  claim 53  wherein the alternative complement pathway activation product is C3a or C5a.  
     
     
         56 . The use of  claim 53  wherein the anti-properdin agent is an anti-properdin antibody.  
     
     
         57 . The use of  claim 53  wherein the anti-properdin agent is an antigen-binding fragment of an anti-properdin antibody.  
     
     
         58 . The use of  claim 53  wherein the anti-properdin agent is a properdin-derived peptide.  
     
     
         59 . The process of  claim 53  wherein the anti-properdin agent lacks the ability to activate Fcγ receptors.  
     
     
         60 . Use of an alternative pathway C3 convertase-inhibiting agent in the preparation of medicament for selectively inhibiting formation of an alternative complement pathway activation product in a subject in which the classical complement pathway is initiated.  
     
     
         61 . The use of  claim 60  wherein the alternative complement pathway activation product is MAC.  
     
     
         62 . The use of  claim 60  wherein the alternative complement pathway activation product is C3a.  
     
     
         63 . The use of  claim 60  wherein the agent is an anti-properdin antibody.  
     
     
         64 . The use of  claim 60  wherein the agent is an antigen-binding fragment of an anti-properdin antibody.  
     
     
         65 . The use of  claim 60  wherein the agent is a properdin-derived peptide.  
     
     
         66 . The use of  claim 60  wherein the agent lacks the ability to activate Fcγ receptors.  
     
     
         67 . A pharmaceutical composition comprising (a) an anti-properdin antibody or an antigen-binding fragment of an anti-properdin antibody that (1) selectively inhibits formation of an alternative complement pathway activation product; and (2) does not substantially activate Fcγ receptors, and (b) a pharmaceutically acceptable carrier.  
     
     
         68 . The pharmaceutical composition of  claim 67  wherein the alternative complement pathway activation product is MAC.  
     
     
         69 . The pharmaceutical composition of  claim 67  wherein the alternative complement pathway activation product is C3a or C5a.  
     
     
         70 . The pharmaceutical composition of  claim 67  wherein the anti-properdin antibody is a monoclonal anti-properdin antibody.  
     
     
         71 . The pharmaceutical composition of  claim 70  wherein the monoclonal anti-properdin antibody has the human γ4 IgG isotype.  
     
     
         72 . The pharmaceutical composition of  claim 67  wherein the antigen-binding fragment of the anti-properdin antibody is (Fab) 2 .  
     
     
         73 . An anti-properdin agent comprising an anti-properdin antibody or an antigen-binding fragment of an anti-properdin antibody that (a) selectively inhibits formation of an alternative complement pathway activation product, and (b) does not substantially activate Fcγ receptors.  
     
     
         74 . The anti-properdin agent of  claim 73  wherein the alternative complement pathway activation product is MAC.  
     
     
         75 . The anti-properdin agent of  claim 73  wherein the alternative complement pathway activation product is C3a or C5a.  
     
     
         76 . The anti-properdin agent of  claim 73  wherein the anti-properdin agent is a monoclonal antibody.  
     
     
         77 . The anti-properdin agent of  claim 76  wherein the monoclonal anti-properdin antibody has the human γ4 IgG isotype.  
     
     
         78 . The anti-properdin agent of  claim 73  wherein the antigen-binding fragment of the anti-properdin antibody is (Fab) 2 .  
     
     
         79 . A method of screening for and selecting an anti-properdin agent comprising (a) assaying the agent for its ability to inhibit formation of an alternative complement pathway activation product; (b) assaying the agent for its ability to activate Fcγ receptors; and (c) selecting the agent that inhibits the formation of an alternative complement pathway activation product and does not substantially activate Fcγ receptors.  
     
     
         80 . The method of  claim 79  wherein the alternative complement pathway activation product is MAC.  
     
     
         81 . The method of  claim 79  wherein the alternative complement pathway activation product is C3a or C5a.  
     
     
         82 . The method of  claim 79  wherein the anti-properdin agent is a monoclonal antibody.  
     
     
         83 . The method of  claim 82  wherein the monoclonal anti-properdin antibody has the human γ4 IgG isotype.  
     
     
         84 . The method of  claim 79  wherein the antigen-binding fragment of the anti-properdin antibody is (Fab) 2 .