THERAPEUTIC METHODS AND USES FOR ANTIBODIES TO HUMAN MASP-3
Methods of treating paroxysmal nocturnal hemoglobinuria, complement 3 glomerulopathy, or idiopathic immune complex-mediated glomerulonephritis using MASP-3 serine protease inhibitors are provided. In some embodiments, the MASP-3 serine protease inhibitors are anti-MASP-3 antibodies. Also provided are uses of MASP-3 serine protease inhibitors in treatment of paroxysmal nocturnal hemoglobinuria, complement 3 glomerulopathy, or idiopathic immune complex-mediated glomerulonephritis and for manufacture of a medicament for treatment of paroxysmal nocturnal hemoglobinuria, complement 3 glomerulopathy, or idiopathic immune complex-mediated glomerulonephritis.
1 . A method for treating a human subject suffering from paroxysmal nocturnal hemoglobinuria (PNH), the method comprising administering to the subject an amount of a MASP-3 inhibitory agent sufficient to inhibit alternative pathway complement activation.
2 . The method of claim 1 , wherein the subject exhibits a sub-optimal response to treatment with a C5 inhibitor.
3 . The method of claim 2 , wherein the C5 inhibitor is eculizumab, ravulizumab, or a biosimilar to either eculizumab or ravulizumab.
4 . The method of claim 2 , wherein the subject exhibits a hemoglobin level of less than 10.5 g/dL in response to C5 inhibitor treatment.
5 . The method of claim 1 , wherein the MASP-3 inhibitory agent is an anti-MASP-3 antibody or antigen-binding fragment thereof.
6 . The method of claim 5 , wherein the anti-MASP-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising an HCDR1 having the sequence set forth as SEQ ID NO:3, an HCDR2 having the sequence set forth as SEQ ID NO:4 or 11, and an HCDR3 having the sequence set forth as SEQ ID NO:5 and a light chain variable region comprising an LCDR1 having the sequence set forth as SEQ ID NO: 6 or 14, an LCDR2 having the sequence set forth as SEQ ID NO:7, and an LCDR3 having the sequence set forth as SEQ ID NO:8.
7 . The method of claim 6 , wherein the anti-MASP-3 antibody or antigen-binding fragment thereof comprises an HCDR1 having the sequence set forth as SEQ ID NO:3, an HCDR2 having the sequence set forth as SEQ ID NO:4, an HCDR3 having the sequence set forth as SEQ ID NO:5, an LCDR1 having the sequence set forth as SEQ ID NO:6, an LCDR2 having the sequence set forth as SEQ ID NO:7, and an LCDR3 having the sequence set forth as SEQ ID NO:8.
8 . (canceled)
9 . (canceled)
10 . The method of claim 6 , wherein the anti-MASP-3 antibody or antigen-binding fragment thereof comprises an HCDR1 having the sequence set forth as SEQ ID NO:3, an HCDR2 having the sequence set forth as SEQ ID NO: 11, an HCDR3 having the sequence set forth as SEQ ID NO:5, an LCDR1 having the sequence set forth as SEQ ID NO:6, an LCDR2 having the sequence set forth as SEQ ID NO:7, and an LCDR3 having the sequence set forth as SEQ ID NO:8.
11 . (canceled)
12 . The method of claim 6 , wherein the anti-MASP-3 antibody or antigen-binding fragment thereof comprises an HCDR1 having the sequence set forth as SEQ ID NO:3, an HCDR2 having the sequence set forth as SEQ ID NO:11, and an HCDR3 having the sequence set forth as SEQ ID NO:5, an LCDR1 having the sequence set forth as SEQ ID NO:14, an LCDR2 having the sequence set forth as SEQ ID NO:7, and an LCDR3 having the sequence set forth as SEQ ID NO:8.
13 . (canceled)
14 . The method of claim 6 , wherein the anti-MASP-3 antibody or antigen-binding fragment thereof comprises an HCDR1 having the sequence set forth as SEQ ID NO:3, an HCDR2 having the sequence set forth as SEQ ID NO:4, an HCDR3 having the sequence set forth as SEQ ID NO:5, an LCDR1 having the sequence set forth as SEQ ID NO:14, an LCDR2 having the sequence set forth as SEQ ID NO:7, and an LCDR3 having the sequence set forth as SEQ ID NO:8.
15 . (canceled)
16 . (canceled)
17 . The method of claim 1 , wherein the MASP-3 inhibitory agent is administered subcutaneously or intravenously.
18 . The method of claim 1 , wherein the MASP-3 inhibitory agent is administered at intervals of 4 to 16 weeks.
19 . (canceled)
20 . (canceled)
21 . (canceled)
22 . The method of claim 1 , wherein the MASP-3 inhibitory agent is administered at a dosage of 1 mg/kg to 25 mg/kg.
23 . The method of claim 22 , wherein the MASP-3 inhibitory agent is administered at a dosage of 1 mg/kg to 15.0 mg/kg.
24 . (canceled)
25 . (canceled)
26 . (canceled)
27 . (canceled)
28 . The method of claim 1 , wherein the subject receives both a MASP-3 inhibitory agent and a second complement inhibitor.
29 . The method of claim 28 , wherein the second complement inhibitor is a C5 inhibitor.
30 . (canceled)
31 . A method for treating a human subject suffering from complement 3 glomerulopathy (C3G) or idiopathic immune complex-mediated glomerulonephritis (ICGN), the method comprising administering to the subject an amount of a MASP-3 inhibitory agent sufficient to inhibit alternative pathway complement activation.
32 . The method of claim 31 , wherein the MASP-3 inhibitory agent is an anti-MASP-3 antibody or antigen-binding fragment thereof.
33 . The method of claim 32 , wherein the anti-MASP-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising an HCDR1 having the sequence set forth as SEQ ID NO:3, an HCDR2 having the sequence set forth as SEQ ID NO:4 or 11, and an HCDR3 having the sequence set forth as SEQ ID NO:5 and a light chain variable region comprising an LCDR1 having the sequence set forth as SEQ ID NO: 6 or 14, an LCDR2 having the sequence set forth as SEQ ID NO:7, and an LCDR3 having the sequence set forth as SEQ ID NO:8.
34 . The method of claim 33 , wherein the anti-MASP-3 antibody or antigen-binding fragment thereof comprises an HCDR1 having the sequence set forth as SEQ ID NO:3, an HCDR2 having the sequence set forth as SEQ ID NO:4, an HCDR3 having the sequence set forth as SEQ ID NO:5, an LCDR1 having the sequence set forth as SEQ ID NO:6, an LCDR2 having the sequence set forth as SEQ ID NO:7, and an LCDR3 having the sequence set forth as SEQ ID NO:8.
35 . (canceled)
36 . (canceled)
37 . The method of claim 33 , wherein the anti-MASP-3 antibody or antigen-binding fragment thereof comprises an HCDR1 having the sequence set forth as SEQ ID NO:3, an HCDR2 having the sequence set forth as SEQ ID NO: 11, an HCDR3 having the sequence set forth as SEQ ID NO:5, an LCDR1 having the sequence set forth as SEQ ID NO:6, an LCDR2 having the sequence set forth as SEQ ID NO:7, and an LCDR3 having the sequence set forth as SEQ ID NO:8.
38 . (canceled)
39 . The method of claim 33 , wherein the anti-MASP-3 antibody or antigen-binding fragment thereof comprises an HCDR1 having the sequence set forth as SEQ ID NO:3, an HCDR2 having the sequence set forth as SEQ ID NO:11, and an HCDR3 having the sequence set forth as SEQ ID NO:5, an LCDR1 having the sequence set forth as SEQ ID NO:14, an LCDR2 having the sequence set forth as SEQ ID NO:7, and an LCDR3 having the sequence set forth as SEQ ID NO:8.
40 . (canceled)
41 . The method of claim 33 , wherein the anti-MASP-3 antibody or antigen-binding fragment thereof comprises an HCDR1 having the sequence set forth as SEQ ID NO:3, an HCDR2 having the sequence set forth as SEQ ID NO:4, an HCDR3 having the sequence set forth as SEQ ID NO:5, an LCDR1 having the sequence set forth as SEQ ID NO:14, an LCDR2 having the sequence set forth as SEQ ID NO:7, and an LCDR3 having the sequence set forth as SEQ ID NO:8.
42 . (canceled)
43 . (canceled)
44 . The method of claim 31 , wherein the MASP-3 inhibitory agent is administered subcutaneously or intravenously.
45 . The method of claim 31 , wherein the MASP-3 inhibitory agent is administered at intervals of 4 to 16 weeks.
46 . (canceled)
47 . (canceled)
48 . (canceled)
49 . (canceled)
50 . The method of claim 31 , wherein the MASP-3 inhibitory agent is administered at a dosage of 1 mg/kg to 25.0 mg/kg.
51 . The method of claim 50 , wherein the MASP-3 inhibitory agent is administered at a dosage of 1.0 mg/kg to 15.0 mg/kg.
52 . (canceled)
53 . (canceled)
54 . (canceled)
55 . (canceled)
56 . (canceled)
57 . The method of claim 1 or claim 31 , wherein a pharmaceutical composition is administered to the subject, the pharmaceutical composition comprising a MASP-3 inhibitory antibody, or antigen-binding fragment thereof, in an aqueous solution.
58 . The method of claim 57 , wherein the pharmaceutical composition comprises a MASP-3 inhibitory antibody, or antigen-binding fragment thereof, in an aqueous solution comprising a buffer system having a pH of 6.0±5%, 20±5% mM histidine, 100±5% mg/mL sucrose, and 0.035±5% polysorbate 80 (w/w).
59 . The method of claim 57 , wherein the MASP-3 inhibitory antibody, or antigen-binding fragment thereof, is included in the pharmaceutical composition at a concentration of 110 mg/mL±5%.
60 . (canceled)
61 . (canceled)
62 . (canceled)
63 . (canceled)
64 . (canceled)
65 . (canceled)