Inhibition of factor b, the alternative complement pathway and methods related thereto

Abstract

Disclosed are novel inhibitors of the alternative complement pathway and particularly, novel anti-factor B antibodies. Also disclosed is the use of such inhibitors to reduce or prevent airway hyperresponsiveness and/or airway inflammation by selectively inhibiting the alternative complement pathway, thereby treating diseases in which such conditions play a role. Also disclosed is the use of such inhibitors to reduce or prevent other diseases and conditions, including ischemia-reperfusion injury, by inhibition of the alternative complement pathway.

What is claimed is: 
     
         1 . An isolated antibody or antigen-binding fragment thereof that selectively binds to factor B within the third short consensus repeat (SCR) domain, wherein the antibody prevents formation of a C3bBb complex. 
     
     
         2 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof binds to factor B and prevents or inhibits cleavage of factor B by factor D. 
     
     
         3 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen binding fragment bind to the third short consensus repeat (SCR) domain of human factor B. 
     
     
         4 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen binding fragment thereof selectively binds to an epitope in the third SCR domain of factor B selected from the group consisting of:
 a) an epitope of factor B that includes at least a portion of human factor B (SEQ ID NO:2) comprising from about position Tyr139 to about position Ser185, or equivalent positions thereto in a non-human factor B sequence;   b) an epitope of factor B that includes at least a portion of human factor B (SEQ ID NO:2) comprising from about position Tyr139 to about position Ser141, or equivalent positions thereto in a non-human factor B sequence;   c) an epitope of factor B that includes at least a portion of human factor B (SEQ ID NO:2) comprising from about position Glu182 to about position Ser185, or equivalent positions thereto in a non-human factor B sequence; and   d) an epitope of factor B that includes at least a portion of human factor B (SEQ ID NO:2) comprising any one or more of the following positions or their equivalent positions in a non-human factor B sequence: Tyr139, Cys 140, Ser141, Glu182, Gly184, or Ser185.   
     
     
         5 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen binding fragment thereof selectively binds to an epitope in the third SCR domain of factor B (SEQ ID NO:2) comprising one or more of the following amino acid positions or their equivalent positions in a non-human factor B sequence: Ala137, Tyr139, Ser141, Glu182, Ser185, Thr189, Glu190, and Ser192. 
     
     
         6 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen binding fragment thereof selectively binds to an epitope in the third SCR domain of factor B (SEQ ID NO:2) comprising the following amino acid positions or their equivalent positions in a non-human factor B sequence: Ala137, Tyr139, Ser141, Glu182, Ser185, Thr189, Glu190, and Ser192. 
     
     
         7 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen binding fragment thereof selectively binds to an epitope in the third SCR domain of factor B (SEQ ID NO:2) consisting of the following amino acid positions or their equivalent positions in a non-human factor B sequence: Ala137, Tyr139, Ser141, Glu182, Ser185, Thr189, Glu190, and Ser192. 
     
     
         8 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen binding fragment thereof selectively binds to a non-linear epitope within the three-dimensional structure of a portion of the third SCR domain of factor B, wherein the portion is defined by at least amino acid positions Ala137-Ser192 of SEQ ID NO:2 or equivalent positions in a non-human factor B sequence. 
     
     
         9 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen binding fragment thereof selectively binds to factor B from multiple mammalian species. 
     
     
         10 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen binding fragment thereof selectively binds to factor B from human and an animal selected from the group consisting of non-human primate, mouse, rat, pig, horse and rabbit. 
     
     
         11 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody is of a non-complement activating isotype or subclass. 
     
     
         12 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody is a monoclonal antibody. 
     
     
         13 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antigen binding fragment is an Fab fragment. 
     
     
         14 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody is a humanized antibody. 
     
     
         15 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody is a bispecific antibody. 
     
     
         16 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody is a monovalent antibody. 
     
     
         17 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody is the monoclonal antibody 1379 (produced by ATCC Deposit No. PTA-6230). 
     
     
         18 . A composition comprising the isolated antibody or antigen binding fragment thereof, of  claim 1 . 
     
     
         19 . An isolated antibody or antigen-binding fragment thereof that selectively binds to factor B from multiple mammalian species, wherein the antibody prevents formation of a C3bBb complex. 
     
     
         20 . The isolated antibody or antigen-binding fragment thereof of  claim 19 , wherein the antibody or antigen binding fragment thereof selectively binds to factor B from human and an animal selected from the group consisting of non-human primate, mouse, rat, pig, horse and rabbit. 
     
     
         21 . The isolated antibody or antigen-binding fragment thereof of  claim 19 , wherein the antibody is of a non-complement activating isotype or subclass. 
     
     
         22 . The isolated antibody or antigen-binding fragment thereof of  claim 19 , wherein the antibody is a monoclonal antibody. 
     
     
         23 . The isolated antibody or antigen-binding fragment thereof of  claim 19 , wherein the antigen binding fragment is an Fab fragment. 
     
     
         24 . A composition comprising the isolated antibody or antigen binding fragment thereof, of  claim 19 . 
     
     
         25 . An antigen binding polypeptide that selectively binds to factor B within the third short consensus repeat (SCR) domain, wherein the antigen binding polypeptide prevents formation of a C3bBb complex. 
     
     
         26 . An antigen binding polypeptide that selectively binds to factor B from multiple mammalian species, wherein the antigen binding polypeptide prevents formation of a C3bBb complex. 
     
     
         27 . A composition comprising the antigen binding polypeptide of  claim 25 . 
     
     
         28 . A composition comprising the antigen binding polypeptide of  claim 26 . 
     
     
         29 . An isolated antibody or antigen binding fragment thereof that selectively binds to factor B, wherein the antibody or fragment thereof competitively inhibits the specific binding of the monoclonal antibody 1379 (produced by ATCC Deposit No. PTA-6230) to human factor B, and wherein, when the antibody or antigen binding fragment thereof binds to human factor B, the ability of monoclonal antibody 1379 to inhibit the alternative complement pathway is inhibited. 
     
     
         30 . The antibody or antigen binding fragment thereof according to  claim 29 , wherein the antibody or antigen binding fragment thereof competitively inhibits the binding of monoclonal antibody 1379 to human factor B, where comparative binding specificity is determined by antibody-antibody competition assay in the presence of human factor B. 
     
     
         31 . An isolated antibody or fragment thereof that selectively binds to human factor B, wherein the isolated antibody or fragment thereof competitively inhibits the specific binding of a second antibody or antigen binding fragment thereof to human factor B, and wherein the second antibody or antigen binding fragment thereof binds to the third SCR domain of human factor B. 
     
     
         32 . A method to reduce or prevent airway hyperresponsiveness (AHR) or airway inflammation in an animal, comprising administering an antibody or antigen binding fragment thereof according to  claim 1  to an animal that has, or is at risk of developing, airway hyperresponsiveness associated with inflammation or airway inflammation. 
     
     
         33 . The method of  claim 32 , wherein the antibody or antigen binding fragment is administered by a route selected from the group consisting of oral, nasal, topical, inhaled, intratracheal, transdermal, rectal and parenteral routes. 
     
     
         34 . The method of  claim 32 , wherein the antibody or antigen binding fragment is administered to the animal in an amount effective to measurably reduce airway hyperresponsiveness in the animal as compared to prior to administration of the antibody or antigen binding fragment. 
     
     
         35 . The method of  claim 32 , wherein the antibody or antigen binding fragment is administered to the animal in an amount effective to measurably reduce airway hyperresponsiveness in the animal as compared to a level of airway hyperresponsiveness in a population of animals having inflammation wherein the antibody or antigen binding fragment was not administered. 
     
     
         36 . The method of  claim 32 , wherein administration of the antibody or antigen binding fragment decreases the animal's responsiveness to methacholine or to histamine. 
     
     
         37 . The method of  claim 32 , wherein the antibody or antigen binding fragment is administered with a pharmaceutically acceptable carrier selected from the group consisting of: a dry, dispersible powder; anhydrous ethanol; small capsules; liposomes; a nebulized spray; and an injectable excipient. 
     
     
         38 . The method of  claim 32 , wherein the antibody or antigen binding fragment is administered in a carrier or device selected from the group consisting of: anhydrous ethanol; a dry powder inhalation system; ultrasonic inhalation system; a pressurized metered dose inhaler; and a metered solution device. 
     
     
         39 . The method of  claim 32 , wherein said antibody or antigen binding fragment is administered to said mammal in conjunction with an agent selected from the group consisting of: corticosteroids, β-agonists (long or short acting), leukotriene modifiers, antihistamines, phosphodiesterase inhibitors, sodium cromoglycate, Nedocromil, theophylline, cytokine antagonists, cytokine receptor antagonists, anti-IgE, and inhibitors of T cell function. 
     
     
         40 . The method of  claim 32 , wherein said airway hyperresponsiveness or airway inflammation is associated with a disease selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), allergic bronchopulmonary aspergillosis, hypersensitivity pneumonia, eosinophilic pneumonia, emphysema, bronchitis, allergic bronchitis bronchiectasis, cystic fibrosis, tuberculosis, hypersensitivity pneumonitis, occupational asthma, sarcoid, reactive airway disease syndrome, interstitial lung disease, hyper-eosinophilic syndrome, rhinitis, sinusitis, exercise-induced asthma, pollution-induced asthma, cough variant asthma, parasitic lung disease, respiratory syncytial virus (RSV) infection, parainfluenza virus (PTV) infection, rhinovirus (RV) infection and adenovirus infection. 
     
     
         41 . The method of  claim 32 , wherein the airway hyperresponsiveness is associated with allergic inflammation. 
     
     
         42 . The method of  claim 32 , wherein the (AHR) or airway inflammation is associated with asthma. 
     
     
         43 . The method of  claim 32 , wherein the (AHR) or airway inflammation is associated with COPD. 
     
     
         44 . The method of  claim 32 , wherein the animal is a mammal. 
     
     
         45 . The method of  claim 32 , wherein the animal is a human. 
     
     
         46 . A method to reduce or prevent airway hyperresponsiveness (AHR) or airway inflammation in an animal, comprising administering a reagent that selectively inhibits the alternative complement pathway to an animal that has, or is at risk of developing, airway hyperresponsiveness associated with inflammation or airway inflammation.