Method of treating a blood disorder associated with C1q-mediated activation of the classical complement pathway by administering an anti-C1q antibody
The present disclosure relates generally to methods of preventing, reducing risk of developing, or treating a blood disorder (e.g., cold agglutinin hemolytic anemia (cold agglutinin disease), cold antibody hemolytic anemia, ABO incompatible acute hemolytic reactions, warm agglutinin hemolytic anemia, warm antibody hemolytic anemia, warm antibody autoimmune hemolytic anemia (WAIHA)), autoimmune hemolytic anemia (AIHA), autoimmune thrombocytopenia, paroxysmal cold hemoglobinuria (PCH), antiphospholipid syndrome (APS), Evans syndrome, red blood cell alloimmunization, Felty's syndrome, neonatal alloimmune thrombocytopenia, heparin-induced thrombocytopenia (HIT), heparin-induced thrombocytopenia and thrombosis (HITT), thrombotic thrombocytopenic purpura (TTP), immune thrombocytopenic purpura (ITP), thrombocytopenia, thrombosis, vasculitis, lupus nephritis, systemic lupus erythematosus (SLE), glomerulonephritis, anti-phospholipid antibody syndrome (APS), an infection, or a drug-induced hematologic disorder), comprising administering to a subject an inhibitor of the complement pathway.
1 . A method of treating a blood disorder associated with C1q-mediated activation of the classical complement pathway in a subject in need thereof, comprising administering to the subject a Cle inhibitor an anti-C1q antibody, wherein the anti-C1q antibody is a full-length antibody or antigen-binding fragment thereof comprising a light chain variable domain comprising an HVR-L1 having the amino acid sequence of SEQ ID NO: 5, an HVR-L2 having the amino acid sequence of SEQ ID NO: 6, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 7; and a heavy chain variable domain comprising an HVR-H1 having the amino acid sequence of SEQ ID NO: 9, an HVR-H2 having the amino acid sequence of SEQ ID NO: 10, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 11; and wherein:
(i) the full-length antibody is administered to the subject by intravenous injection or infusion once a week, once every other week, or once a month at a dose between 10 mg/kg and 150 mg/kg, or at a dose between 75 mg/kg and 100 mg/kg;
(ii) the full-length antibody is administered to the subject by subcutaneous or intramuscular injection at a dose between 1 mg/kg and 10 mg/kg, or at a dose between 3 mg/kg and 5 mg/kg; or
(iii) the antigen-binding fragment is administered to the subject by intravenous injection or infusion, by intramuscular injection, or by subcutaneous injection at a dose between 0.1 mg/kg and 50 mg/kg, or at a dose between 0.3 mg/kg and 10 mg/kg.
2 . The method of claim 1 , wherein the anti-C1q antibody or antigen-binding fragment thereof is a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a humanized antibody, a human antibody, a chimeric antibody, a monovalent antibody, a multispecific antibody, or antibody derivative thereof.
3 . The method of claim 2 , wherein the anti-C1q antibody is an antigen-binding fragment and the antigen-binding fragment is a Fab fragment, a Fab′ fragment, a F(ab′)2 fragment, a Fv fragment, a diabody, or a single-chain variable fragment.
4 . The method of claim 1 , wherein the anti-C1q antibody or antigen-binding fragment thereof comprises a light chain variable domain comprising an amino acid sequence with at least about 95% sequence identity to the amino acid sequence selected from any one of SEQ ID NO: 4 and 35-38.
5 . The method of claim 4 , wherein the light chain variable domain an amino acid sequence selected from any one of SEQ ID NO: 4 and 35-38.
6 . The method of claim 1 , wherein the anti-C1q antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising an amino acid sequence with at least about 95% sequence identity to the amino acid sequence selected from any one of SEQ ID NO: 8 and 31-34.
7 . The method of claim 6 , wherein the heavy chain variable domain comprises an amino acid sequence selected from any one of SEQ ID NO: 8 and 31-34.
8 . The method of claim 1 , wherein the anti-C1q antibody is an antibody antigen-binding fragment comprising a heavy chain Fab fragment of SEQ ID NO: 39 and a light chain Fab fragment of SEQ ID NO: 40.
9 . The method of claim 1 , wherein the full-length antibody is administered by subcutaneous or intramuscular injection daily, once every other day, once a week, once every other week, or once a month.
10 . The method of claim 1 , wherein the antigen-binding fragment is administered daily, once every other day, once a week, once every other week, or once a month.
11 . The method of claim 10 , wherein the antigen-binding fragment is administered at an initial predose that is higher than the daily, once every other day, once a week, once every other week, or once a month dose.
12 . The method of claim 11 , wherein the initial predose is between 3 mg/kg and 50 mg/kg or between 3 mg/kg and 20 mg/kg.
13 . The method of claim 1 , wherein the blood disorder is cold agglutinin hemolytic anemia (cold agglutinin disease), cold antibody hemolytic anemia, ABO-incompatible acute hemolytic reactions, warm agglutinin hemolytic anemia, warm antibody hemolytic anemia, warm autoimmune hemolytic anemia (WAIHA), autoimmune hemolytic anemia (AIHA), autoimmune thrombocytopenia, paroxysmal cold hemoglobinuria (PCH), antiphospholipid syndrome (APS), Evan's syndrome, neonatal alloimmune thrombocytopenia, red blood cell alloimmunization, Felty's syndrome, antibody-mediated thrombocytopenia, heparin-induced thrombocytopenia (HIT), heparin-induced thrombocytopenia and thrombosis (HITT), thrombotic thrombocytopenia purpura (TTP), immune thrombocytopenia purpura (ITP), thrombocytopenia, thrombosis, vasculitis, lupus nephritis, systemic lupus erythematosus (SLE), glomerulonephritis, anti-phospholipid antibody syndrome (APS), an infection, or a drug-induced hematologic disorder.
14 . The method of claim 1 , wherein the antigen-binding fragment is rapidly cleared, thereby sparing C1q activity outside a subject's blood space.
15 . The method of claim 1 , wherein the anti-C1q antibody or antigen-binding fragment thereof selectively inhibits C1q within a subject's blood space, thereby sparing C1q activity outside the subject's blood space.
16 . The method of claim 14 , wherein the blood space is confined within a blood vessel.
17 . The method of claim 16 , wherein the blood vessel is an artery, an arteriole, a capillary, a venule, or a vein.
18 . The method of claim 14 , wherein the blood space comprises serum, platelets, endothelial cells, blood cells, or hematopoietic cells.
19 . The method of claim 14 , wherein inhibiting C1q within the subject's blood space reduces tissue damage in a highly vascularized tissue.
20 . The method of claim 19 , wherein the highly vascularized tissue is kidney, alveoli, capillary bed, or glomerulus.
21 . The method of claim 1 , wherein the blood disorder is autoimmune thrombocytopenia, cold agglutinin hemolytic anemia (cold agglutinin disease), paroxysmal cold hemoglobinuria (PCH), warm autoimmune hemolytic anemia (WAIHA), or heparin-induced thrombocytopenia (HIT).