ANTI-PROPERDIN ANTIBODIES
A method of inhibiting alternative complement pathway activation in a mammal includes administering an amount of an antibody and/or fragment thereof that specifically binds to an epitope of the N terminus end of properdin effective to the inhibit alternative complement pathway in the subject.
1 - 109 . (canceled)
110 . A method of inhibiting alternative complement pathway activation in blood of a subject, the method comprising: administering to blood of the subject a therapeutically effective amount of an antibody or fragment thereof that specifically binds to an epitope of properdin and promotes dissociation of properdin oligomers to properdin monomers, the antibody or fragment thereof inhibits alternative complement pathway activation without affecting the classical pathway activation and inhibiting binding of properdin to C3b or C3bBb.
111 . The method of claim 110 , wherein the antibody is a monoclonal antibody.
112 . The method of claim 110 , wherein the antibody is administered in vivo or ex vivo.
113 . The method of claim 110 , wherein the antibody is a chimeric, recombinant, humanized, de-immunized or fully human antibody.
114 . The method of claim 110 , wherein the subject has developed or is at risk for developing arthritis.
115 . The method of claim 110 , the antibody or fragment thereof, comprising: a heavy chain variable domain that includes the amino acid sequences of the three CDRs in SEQ ID NO: 7, and a light chain variable domain that includes the amino acid sequences of the three CDRs in SEQ ID NO: 8, wherein the antibody binds to human properdin.
116 . The method of claim 110 , the antibody of fragment thereof exhibiting at least one of the functional properties: reduces the formation of C3bB, the antibody reduces the formation of C3 convertase, reduces the production of C3a and C5a, the antibody reduces C5b-9 complex formation, reduces the activation of neutrophils, the antibody reduces the activation of monocytes, reduces the activation of platelets, or reduces the formation of leukocyte-platelet conjugates.
117 . The method of claim 110 , wherein the antibody or fragment thereof inhibits alternative pathway dependent rabbit erythrocyte lysis in human serum/plasma.
118 . The method of claim 115 , wherein the heavy chain variable regions CDR1, CDR2, and CDR3 comprise the amino acid sequences of SEQ ID NO: 9, 10, and 11, respectively.
119 . The method of claim 115 , wherein the light chain variable regions CDR1, CDR2, and CDR3 comprise the amino acid sequences of SEQ ID NO: 12, 13, and 14, respectively.
120 . The method of claim 110 , wherein the antibody is produced by the hybridoma cell line deposited under ATCC Accession Number PTA-9019.
121 . The method of claim 110 , wherein the antibody or fragment thereof, binds to the same epitope on properdin as an antibody produced by the hybridoma cell line deposited under ATCC Accession Number PTA-9019.
122 . The method of claim 110 , wherein the antibody or fragment thereof is a single chain antibody, IgG, F(ab)2, F(ab′)2, F(ab) fragment, or truncated antibody.
123 . The method of claim 110 , wherein the antibody or fragment thereof lacks the ability to activate Fcγ receptors.
124 . The method of claim 110 , wherein the antibody or fragment thereof lacks immunogenicity in a human.
125 . The method of claim 110 , wherein the antibody or fragment thereof contains more than one antigen binding domain and binds antigen at a stoichiometry of 1:1.
126 . The method of claim 110 wherein the antibody or fragment thereof binds to SEQ ID NO: 2.
127 . The method of claim 110 , wherein the antibody or fragment thereof inhibits alternative pathway mediated formation of TNF alpha.
128 . The method of claim 110 , wherein the antibody or fragment thereof inhibits alternative pathway mediated release of TNF alpha.
129 . The method of claim 110 , wherein the antibody or fragment thereof inhibits alternative pathway mediated release of neutrophil elastase.
130 . The method of claim 110 , wherein the subject has or is at risk of developing atherosclerosis, ischemia-reperfusion following acute myocardial infarction, Henoch-Schonlein purpura nephritis, immune complex vasculitis, rheumatoid arthritis, arteritis, aneurysm, stroke, cardiomyopathy, hemorrhagic shock, crush injury, multiple organ failure, hypovolemic shock and intestinal ischemia, transplant rejection, cardiac Surgery, PTCA, spontaneous abortion, neuronal injury, spinal cord injury, myasthenia gravis, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, Guillain Barre syndrome, Parkinson's disease, Alzheimer's disease, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, transfusion-related acute lung injury, acute lung injury, Goodpasture's disease, myocardial infarction, post-cardiopulmonary bypass inflammation, cardiopulmonary bypass, septic shock, transplant rejection, xeno transplantation, burn injury, systemic lupus erythematosus, membranous nephritis, Berger's disease, psoriasis, pemphigoid, dermatomyositis, anti-phospholipid syndrome, inflammatory bowel disease, hemodialysis, leukopheresis, plasmapheresis, heparin-induced extracorporeal membrane oxygenation LDL precipitation, extracorporeal membrane oxygenation, macular degeneration, and combinations thereof.
131 . A method of inhibiting alternative complement pathway activation in blood of a subject, the method comprising: administering to blood of the subject a therapeutically effective amount of an antibody or fragment thereof that specifically binds to an epitope of properdin that blocks the alternative pathway activation without affecting the classical pathway activation;
inhibits the binding of properdin to C3b or C3bBb;
inhibits AP C3 convertase formation;
inhibits C3a formation;
inhibits C3b deposition;
inhibits Bb deposition;
inhibits C5a formation;
inhibits MAC formation;
inhibits alternative complement pathway-mediated lysis of rabbit erythrocytes;
lowers alternative complement pathway activation levels in plasma in vivo; and
lowers concentration of free properdin in plasma in vivo.
132 . The method of claim 131 wherein the antibody or fragment thereof binds to SEQ ID NO: 2.
133 . The method of claim 131 , wherein the antibody or fragment thereof inhibits alternative pathway mediated formation of TNF alpha.
134 . The method of claim 131 , wherein the antibody or fragment thereof inhibits alternative pathway mediated release of TNF alpha.
135 . The method of claim 131 , wherein the antibody or fragment thereof inhibits alternative pathway mediated release of neutrophil elastase.
136 . The method of claim 131 , wherein the subject has or is at risk of developing atherosclerosis, ischemia-reperfusion following acute myocardial infarction, Henoch-Schonlein purpura nephritis, immune complex vasculitis, rheumatoid arthritis, arteritis, aneurysm, stroke, cardiomyopathy, hemorrhagic shock, crush injury, multiple organ failure, hypovolemic shock and intestinal ischemia, transplant rejection, cardiac Surgery, PTCA, spontaneous abortion, neuronal injury, spinal cord injury, myasthenia gravis, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, Guillain Barre syndrome, Parkinson's disease, Alzheimer's disease, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, transfusion-related acute lung injury, acute lung injury, Goodpasture's disease, myocardial infarction, post-cardiopulmonary bypass inflammation, cardiopulmonary bypass, septic shock, transplant rejection, xeno transplantation, burn injury, systemic lupus erythematosus, membranous nephritis, Berger's disease, psoriasis, pemphigoid, dermatomyositis, anti-phospholipid syndrome, inflammatory bowel disease, hemodialysis, leukopheresis, plasmapheresis, heparin-induced extracorporeal membrane oxygenation LDL precipitation, extracorporeal membrane oxygenation, macular degeneration, and combinations thereof.