Treatment of paroxysmal nocturnal hemoglobinuria patients by an inhibitor of complement

Abstract

Eculizumab, a humanized monoclonal antibody against C5 that inhibits terminal complement activation, showed activity in a preliminary 12-week open-label trial in a small cohort of patients with paroxysmal nocturnal hemoglobinuria (PNH). The present study examined whether chronic eculizumab therapy could reduce intravascular hemolysis, stabilize hemoglobin levels, reduce transfusion requirements, and improve quality of life in a double-blind, randomized, placebo-controlled, multi-center global Phase III trial. It has been found that eculizumab stabilized hemoglobin levels, decreased the need for transfusions, and improved quality of life in PNH patients via reduced intravascular hemolysis. Chronic eculizumab treatment appears to be a safe and effective therapy for PNH.

1 - 90 . (canceled) 
     
     
         91 . A method for treating a patient that: (i) is afflicted with a hemolytic disease and (ii) has been vaccinated against  Neisseria meningitides , the method comprising administering to the patient an effective amount of an anti-C5 antibody that inhibits cleavage of complement component C5 into fragments C5a and C5b. 
     
     
         92 . The method according to  claim 91 , wherein the anti-C5 antibody is a whole antibody or a C5-binding fragment thereof. 
     
     
         93 . The method according to  claim 91 , wherein the anti-C5 antibody is eculizumab. 
     
     
         94 . The method according to  claim 92 , wherein the C5-binding fragment is a Fab, a F(ab)′, a F(ab′) 2 , an scFv, or a diabody. 
     
     
         95 . The method according to  claim 91 , wherein the anti-C5 antibody is pexelizumab. 
     
     
         96 . The method according to  claim 91 , wherein the antibody comprises an altered constant region that exhibits decreased effector function relative to the corresponding native constant region. 
     
     
         97 . The method according to  claim 96 , wherein the effector function is selected from the group consisting of antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). 
     
     
         98 . The method according to  claim 91 , wherein the anti-C5 antibody is administered to the patient for at least 6 months. 
     
     
         99 . The method according to  claim 91 , wherein the hemolytic disease is paroxysmal nocturnal hemoglobinuria (PNH). 
     
     
         100 . The method according to  claim 99 , wherein the patient has a hemoglobin level less than (i) 14 g/dL if a man or (ii) 12 g/dL if a woman. 
     
     
         101 . The method according to  claim 99 , wherein the patient has a hemoglobin level less than (i) 13 g/dL if a man or (ii) 11 g/dL if a woman. 
     
     
         102 . The method according to  claim 99 , wherein the patient has a hemoglobin level less than (i) 12 g/dL if a man or (ii) 10 g/dL if a woman. 
     
     
         103 . The method according to  claim 99 , wherein the patient suffers from hemolysis due to a C3b-mediated, extravascular clearance of PNH erythrocytes through the reticuloendothelial system. 
     
     
         104 . The method according to  claim 99 , wherein the patient is anemic and the anemia results at least in part from extravascular hemolysis, and wherein the patient remains anemic following treatment with the anti-C5 antibody. 
     
     
         105 . The method according to  claim 99 , wherein the patient is at least 18 years of age and has: (i) a PNH type III erythrocyte population of ≧10% and (ii) received at least four transfusions during the 12 months immediately preceding the first treatment with the anti-C5 antibody. 
     
     
         106 . The method according to  claim 91 , wherein the patient has aplastic anemia or myelodysplastic syndrome. 
     
     
         107 . The method according to  claim 92 , wherein the method comprises administering to the patient a pharmaceutical composition comprising a single unit dosage form of the whole anti-C5 antibody or C5-binding fragment thereof, and wherein the single unit dosage form comprises 300 mg of the whole anti-C5 antibody or C5-binding fragment thereof. 
     
     
         108 . The method according to  claim 107 , wherein the single unit dosage form has a volume of 30 mL. 
     
     
         109 . The method according to  claim 107 , wherein the single unit dosage form comprises a 10 mg/mL solution of the anti-C5 antibody or C5-binding fragment thereof. 
     
     
         110 . The method according to  claim 107 , wherein the single unit dosage form is a preservative free formulation. 
     
     
         111 . The method according to  claim 91 , wherein the anti-C5 antibody is to be administered to the patient under the following treatment schedule: (i) 600 mg of the antibody every 7±2 days for the first 4 weeks, (ii) 900 mg of the antibody for the fifth dose 7±2 days after (i), and (iii) 900 mg of the antibody every 14±2 days thereafter, and wherein administration of the antibody to the patient occurs via 25 to 45 minute intravenous infusion. 
     
     
         112 . A method for treating a patient afflicted with a hemolytic disease, the method comprising:
 vaccinating the patient against  Neisseria meningitides ; and   administering to the patient an effective amount of an anti-C5 antibody that inhibits cleavage of complement component C5 into fragments C5a and C5b.   
     
     
         113 . A method for treating a patient afflicted with a hemolytic disease, the method comprising administering to the patient an effective amount of an anti-C5 antibody that: (i) inhibits cleavage of complement component C5 into fragments C5a and C5b and (ii) comprises an altered constant region that exhibits decreased effector function relative to the corresponding native constant region. 
     
     
         114 . The method according to  claim 113 , wherein the effector function is selected from the group consisting of antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). 
     
     
         115 . A method for treating a patient afflicted with a hemolytic disease, the method comprising administering to the patient an anti-C5 antibody under the following treatment schedule: (i) 600 mg of the antibody every 7±2 days for the first 4 weeks, (ii) 900 mg of the antibody for the fifth dose 7±2 days after (i), and (iii) 900 mg of the antibody every 14±2 days thereafter, wherein administration of the antibody to the patient is to occur via 25 to 45 minute intravenous infusion, and wherein the antibody inhibits cleavage of complement component C5 into fragments C5a and C5b.