HUMANEERED ANTI-FACTOR B ANTIBODY
This invention relates to humaneered anti-factor B antibodies and antigen-binding fragments thereof with reduced immunogenicity. The humaneered anti-factor B antibodies and antigen-binding fragments thereof are derived from murine monoclonal antibody 1379, which binds factor B in the third short consensus repeat (“SCR”) domain and selectively inhibits activation of the alternative complement pathway by preventing formation of the C3bBb complex. The invention also relates to methods of treating diseases or disorders in which activation of the alternative complement pathway plays a role, and methods of selectively inhibiting activation of the alternative complement pathway in an individual in need thereof.
1 - 21 . (canceled)
22 . A method of treating a disease or disorder in which activation of the alternative complement pathway plays a role, comprising administering a humaneered anti-factor B antibody or antigen-binding fragment thereof to an individual that has, or is at risk of developing, said disease or disorder, wherein the humaneered anti-factor B antibody or antigen-binding fragment thereof is derived from murine monoclonal antibody 1379 (“mAb 1379”) that selectively binds to factor B within the third short consensus repeat (“SCR”) domain and prevents formation of the C3bBb complex, and wherein the humaneered antibody or antigen-binding fragment thereof has an equilibrium dissociation constant (“K D ”) between about 1.0×10 −8 M and about 1.0×10 −10 M.
23 . The method of claim 22 , wherein the disease or disorder is airway hyperresponsiveness (“AHR”) or airway inflammation.
24 . The method of claim 23 , wherein the humaneered anti-factor B antibody or antigen-binding fragment thereof is administered to the individual in an amount effective to measurably reduce AHR or airway inflammation in the animal as compared to before administration of the antibody or antigen-binding fragment thereof.
25 . The method of claim 24 , wherein said AHR 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 bronchiecstasis, cyctic 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 (“PIV”) infection, rhinovirus (“RV”) infection, and adenovirus infection.
26 . The method of claim 24 , wherein the AHR or airway inflammation is associated with allergic inflammation.
27 . The method of claim 24 , wherein the AHR or airway inflammation is associated with asthma.
28 . The method of claim 24 , wherein the AHR or airway inflammation is associated with COPD.
29 . A method of selectively inhibiting activation of the alternative complement pathway in an individual that has, or is at risk of developing, a condition or disease in which activation of the alternative complement pathway contributes to the condition or disease, exacerbates at least one symptom of the condition or disease, or causes the condition or disease, comprising administering a humaneered anti-factor B antibody or antigen-binding fragment thereof to an individual in need thereof, wherein the humaneered anti-factor B antibody or antigen-binding fragment thereof is derived from murine monoclonal antibody 1379 (“mAb 1379”) that selectively binds to factor B within the third short consensus repeat (“SCR”) domain and prevents formation of the C3bBb complex, and wherein the humaneered antibody or antigen-binding fragment thereof has an equilibrium dissociation constant (“K D ”) between about 1.0×10 −8 M and about 1.0×10 −10 M.
30 . (canceled)
31 . The method of claim 22 , wherein the humaneered antibody or antigen-binding fragment thereof has a K D between about 3.0×10 −9 M and about 7.0×10 −9 M.
32 . The method of claim 22 , wherein the humaneered antibody or antigen-binding fragment thereof comprises a V κ -region polypeptide selected from the group consisting of SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, and SEQ ID NO:20, and a V H -region polypeptide selected from the group consisting of SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, and SEQ ID NO:21.
33 . The method of claim 22 , wherein the antigen-binding fragment is selected from the group consisting of Fab′, (Fab′) 2 , Fv, scFv, and diabodies.
34 . The method of claim 33 , wherein the antigen-binding fragment is a Fab′.
35 . The method of claim 22 , wherein the humaneered antibody or antigen-binding fragment thereof comprises a V κ -region comprising a binding specificity determinant (“BSD”) derived from the CDR3-FR4 region selected from the group consisting of SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO. 26, and SEQ ID NO. 28 and a V H -region comprising a BSD derived from the CDR3-FR4 region selected from the group consisting of SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 27, and SEQ ID NO. 29.
36 . The method of claim 35 , wherein the antigen-binding fragment is selected from the group consisting of Fab′, (Fab′) 2 , Fv, scFv, and diabodies.
37 . The method of claim 36 , wherein the antigen-binding fragment is a Fab′.
38 . The method of claim 29 , wherein the humaneered antibody or antigen-binding fragment thereof has a K D between about 3.0×10 −9 M and about 7.0×10 −9 M.
39 . The method of claim 29 , wherein the humaneered antibody or antigen-binding fragment thereof comprises a V κ -region polypeptide selected from the group consisting of SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, and SEQ ID NO:20, and a V H -region polypeptide selected from the group consisting of SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, and SEQ ID NO:21.
40 . The method of claim 29 , wherein the antigen-binding fragment is a Fab′.
41 . The method of claim 29 , wherein the humaneered antibody or antigen-binding fragment thereof comprises a V κ -region comprising a binding specificity determinant (“BSD”) derived from the CDR3-FR4 region selected from the group consisting of SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO. 26, and SEQ ID NO. 28 and a V H -region comprising a BSD derived from the CDR3-FR4 region selected from the group consisting of SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 27, and SEQ ID NO. 29.
42 . The method of claim 41 , wherein the antigen-binding fragment is a Fab′.