Compositions and Methods of Inhibiting MASP-1 and/or MASP-2 and/or MASP-3 for the Treatment of Paroxysmal Nocturnal Hemoglobinuria
In one aspect, the invention provides methods and compositions for inhibiting MASP-3-dependent complement activation in a subject suffering from paroxysmal nocturnal hemoglobinuria by administering to the subject a composition comprising an amount of a MASP-3 inhibitory agent in an amount effective to inhibit MASP-3-dependent complement activation. In another aspect, the invention provides methods and compositions for increasing the survival of red blood cells in a subject suffering from paroxysmal nocturnal hemoglobinuria by administering to the subject a composition comprising an amount of at least one of a MASP-1 inhibitory agent and/or a MASP-3 inhibitory agent effective to increase the survival of red blood cells. In some embodiments, the subject is administered a MASP-2 inhibitory agent and a MASP-1 inhibitory agent, a MASP-2 inhibitory agent and a MASP-3 inhibitory agent administered, a MASP-3 inhibitory agent and a MASP-1 inhibitory agent, or a MASP-1 inhibitory agent, a MASP-2 inhibitory agent and a MASP-3 inhibitory agent.
1 . A method of inhibiting MASP-3-dependent complement activation in a subject suffering from paroxysmal nocturnal hemoglobinuria (PNH), comprising administering to the subject a composition comprising an amount of a MASP-3 inhibitory agent effective to inhibit MASP-3-dependent complement activation.
2 . The method of claim 1 , wherein the MASP-3 inhibitory agent is a MASP-3 monoclonal antibody, or fragment thereof that specifically binds to a portion of SEQ ID NO:8.
3 . The method of claim 1 , further comprising administering to the subject a composition comprising a MASP-1 inhibitory agent.
4 . The method of claim 3 , wherein the MASP-1 inhibitory agent is a MASP-1 monoclonal antibody, or fragment thereof, that specifically binds to a portion of SEQ ID NO:10.
5 . The method of claim 1 , further comprising administering to the subject a composition comprising a MASP-2 inhibitory agent.
6 . The method of claim 5 , wherein the MASP-2 inhibitory agent is a MASP-2 monoclonal antibody, or fragment thereof that specifically binds to a portion of SEQ ID NO:5.
7 . The method of claim 1 , further comprising administering to the subject a composition comprising a MASP-1 inhibitory agent and a MASP-2 inhibitory agent.
8 . The method of any one of claims 1 - 7 , wherein the composition increases the survival of red blood cells in the subject.
9 . The method of claim 8 , wherein the subject exhibits one or more symptoms selected from the group consisting of (i) below normal levels of hemoglobin, (ii) below normal levels of platelets; (iii) above normal levels of reticulocytes, and (iv) above normal levels of bilirubin.
10 . The method of claim 1 , wherein the subject has previously undergone, or is currently undergoing treatment with a terminal complement inhibitor that inhibits cleavage of complement protein C5.
11 . The method of claim 1 , wherein the method further comprises administering to the subject a terminal complement inhibitor that inhibits cleavage of complement protein C5.
12 . The method of claim 11 , wherein the terminal complement inhibitor is a humanized anti-C5 antibody or antigen-binding fragment thereof.
13 . The method of claim 12 , wherein the terminal complement inhibitor is eculizumab.
14 . The method of claim 1 , wherein the MASP-3 inhibitory agent inhibits alternative-pathway driven C3b deposition.
15 . The method of claim 1 , wherein the MASP-3 inhibitory agent inhibits factor D maturation.
16 . The method of claim 3 , wherein the MASP-1 inhibitory agent specifically binds to a portion of MASP-1 with an affinity of at least 10 times greater than it binds to MASP-3 (SEQ ID NO:8).
17 . The method of claim 3 , wherein the MASP-1 inhibitory agent specifically binds to the serine protease domain of MASP-1 (aa 449-694 of SEQ ID NO:10).
18 . The method of claim 1 , wherein the MASP-3 inhibitory agent also binds to a portion of MASP-1 (SEQ ID NO:10).
19 . The method of claim 18 , wherein the MASP-3 inhibitory agent is a dual MASP-1/MASP-3 inhibitor that binds to a consensus region within the CUBI-CCP2 domains.
20 . The method of claim 18 , wherein the MASP-3 inhibitory agent is a dual MASP-1/MASP-3 inhibitor that binds to a consensus region within the CCP2 domain.
21 . The method of claim 18 , wherein the MASP-3 inhibitory agent is a bi-specific monoclonal antibody that binds to the serine protease domain of MASP-1 (aa 449-694 of SEQ ID NO:10) and also binds to the serine protease domain of MASP-3 (aa 450-711 of SEQ ID NO:8).
22 . The method of claim 1 , wherein the MASP-3 inhibitory agent also binds to a portion of MASP-2 (SEQ ID NO:5).
23 . The method of claim 22 , wherein the MASP-3 inhibitory agent is a dual MASP-3/MASP-2 inhibitor that binds to a conserved region within the serine protease domains of MASP-3 and MASP-2.
24 . The method of claim 22 , wherein the MASP-3 inhibitory agent is a bispecific monoclonal antibody that binds to the serine protease domain of MASP-3 (aa450-711 of SEQ ID NO:8) and also binds to at least one of the serine protease domain of MASP-2 (aa 445-682 of SEQ ID NO:5) or the CCP-1-CCP2 domain of MASP-2 (aa300-431 of SEQ ID NO:5).
25 . The method of claim 1 , wherein the MASP-3 inhibitory agent binds to a portion of MASP-3 (SEQ ID NO:8) and does not inhibit MASP-1 or MASP-2.
26 . The method of claim 1 , wherein the MASP-3 inhibitory agent specifically binds to a portion of MASP-3 with an affinity of at least 10 times greater than it binds to MASP-1 (SEQ ID NO:10).
27 . The method of claim 1 , wherein the MASP-3 inhibitory agent specifically binds to the serine protease domain of MASP-3 (aa 450-711 of SEQ ID NO:8).
28 . The method of claim 1 , wherein the MASP-3 inhibitory agent is a pan inhibitor of MASP-1, MASP-2 and MASP-3 and binds to a conserved region in the CUB1-EGF-CUB2 domains.
29 . The method of claim 1 , wherein the MASP-3 inhibitory agent is a trispecific inhibitor of MASP-1, MASP-2 and MASP-3.
30 . The method of claim 2 , wherein the composition further comprises a MASP-2 antibody.
31 . The method of claim 2 , wherein the composition further comprises a MASP-1 antibody.
32 . The method of claim 7 , wherein the composition comprises a MASP-1 antibody, and MASP-2 antibody and a MASP-3 antibody.
33 . The method of claim 7 , wherein the method comprises co-administration of a composition comprising at least one of a MASP-2 antibody, a MASP-1 antibody, or a MASP-3 antibody.
34 . The method of claim 18 , wherein the composition further comprises a MASP-2 antibody.
35 . The method of claim 22 , wherein the composition further comprises a MASP-1 antibody.
36 . The method of claim 1 , wherein the antibody or fragment thereof is selected from the group consisting of a recombinant antibody, an antibody having reduced effector function, a chimeric, and a humanized or human antibody.
37 . The method of claim 1 , wherein the composition is administered systemically.
38 . The method of claim 37 , wherein the composition is administered subcutaneously, intra-muscularly, intravenously, intra-arterially or as an inhalant.
39 . A method of increasing the survival of red blood cells in a subject suffering from paroxysmal nocturnal hemoglobinuria (PNH), comprising administering to the subject a composition comprising an amount of at least one of a MASP-1 inhibitory agent and/or a MASP-3 inhibitory agent effective to increase the survival of red blood cells.
40 . The method of claim 39 , wherein the composition comprises a MASP-1 inhibitory agent.
41 . The method of claim 39 , wherein the composition comprises a MASP-3 inhibitory agent.
42 . The method of claim 39 , wherein the composition comprises a MASP-1 inhibitory agent and a MASP-3 inhibitory agent.
43 . The method of claim 39 , further comprising administering to the subject a composition comprising a MASP-2 inhibitory agent.
44 . The method of claim 40 , wherein the MASP-1 inhibitory agent is a MASP-1 monoclonal antibody.
45 . The method of claim 41 , wherein the MASP-3 inhibitory agent is a MASP-3 monoclonal antibody.
46 . The method of claim 43 , wherein the MASP-2 inhibitory agent is a MASP-2 monoclonal antibody.
47 . A pharmaceutical composition comprising at least one complement pathway inhibitory agent, wherein the at least one inhibitory agent comprises a MASP-2 inhibitory agent and at least one of a MASP-3 inhibitory agent and/or a MASP-1 inhibitory agent and a pharmaceutically acceptable carrier.
48 . The pharmaceutical composition of claim 47 , wherein the at least one inhibitory agent comprises a combination of a first molecule that is a MASP-3 inhibitory agent and a second molecule that is a MASP-2 inhibitory agent.
49 . The pharmaceutical composition of claim 47 , wherein the at least one inhibitory agent comprises a single molecular entity that includes activity as a MASP-3 inhibitory agent and activity as a MASP-2 inhibitory agent.
50 . The pharmaceutical composition of claim 47 , wherein the MASP-3 inhibitory agent is a MASP-3 monoclonal antibody, or fragment thereof.
51 . The pharmaceutical composition of claim 47 , wherein the MASP-2 inhibitory agent is a MASP-2 antibody, or fragment thereof.
52 . The pharmaceutical composition of claim 47 , wherein the MASP-3 inhibitory agent inhibits MASP-3-mediated cleavage of factor B.
53 . The pharmaceutical composition of claim 47 , wherein the MASP-3 inhibitory agent inhibits factor D maturation.
54 . The pharmaceutical composition of claim 47 , wherein the MASP-1 inhibitory agent is a MASP-1 antibody, or fragment thereof.
55 . The pharmaceutical composition of claim 47 , wherein the MASP-1 inhibitory agent specifically binds to a portion of MASP-1 with an affinity of at least 10 times greater than it binds to MASP-3 (SEQ ID NO:8).
56 . The pharmaceutical composition of claim 47 , wherein the MASP-1 inhibitory agent specifically binds to the serine protease domain of MASP-1 (aa 449-694 of SEQ ID NO:10).
57 . The pharmaceutical composition of claim 47 , wherein the MASP-1 inhibitory agent also binds to a portion of MASP-3 (SEQ ID NO:8). 58. The pharmaceutical composition of claim 57 , wherein the MASP-3 inhibitory agent is a dual MASP-1/MASP-3 inhibitor that binds to a consensus region within the CUBI-CCP2 domains.
59 . The pharmaceutical composition of claim 57 , wherein the MASP-3 inhibitory agent is a dual MASP-1/MASP-3 inhibitor that binds to a consensus region within the CCP2 domain.
60 . The pharmaceutical composition of claim 57 , wherein the MASP-3 inhibitory agent is a bispecific monoclonal antibody that binds to the serine protease domain of MASP-1 (aa 449-694 of SEQ ID NO:10) and also binds to the serine protease domain of MASP-3 (aa 450-711 of SEQ ID NO:8).
61 . The pharmaceutical composition of claim 47 , wherein the MASP-1 inhibitory agent also binds to a portion of MASP-2 (SEQ ID NO:5).
62 . The pharmaceutical composition of claim 61 , wherein the MASP-1 inhibitory agent is a dual MASP-1/MASP-2 inhibitor that binds to a conserved region within the serine protease domains of MASP-1 and MASP-2.
63 . The pharmaceutical composition of claim 61 , wherein the MASP-1 inhibitory agent is a bispecific monoclonal antibody that binds to the serine protease domain of MASP-1 (aa449-694 of SEQ ID NO:10) and also binds to at least one of the serine protease domain of MASP-2 (aa 445-682 of SEQ ID NO:5) or the CCP-1-CCP2 domain of MASP-2 (aa300-431 of SEQ ID NO:5).
64 . The pharmaceutical composition of claim 47 , wherein the MASP-3 inhibitory agent specifically binds to a portion of MASP-3 (SEQ ID NO:8: full-length).
65 . The pharmaceutical composition of claim 47 , wherein the MASP-3 inhibitory agent specifically binds to a portion of MASP-3 with an affinity of at least 10 times greater than it binds to MASP-1 (SEQ ID NO:10).
66 . The pharmaceutical composition of claim 64 , wherein the MASP-3 inhibitory agent specifically binds to the serine protease domain of MASP-3 (aa 450-711 of SEQ ID NO:8).
67 . The pharmaceutical composition of claim 47 , wherein the MASP-3 inhibitory agent also binds to a portion of MASP-2 (SEQ ID NO:5).
68 . The pharmaceutical composition of claim 67 , wherein the MASP-3 inhibitory agent is a dual MASP-2/MASP-3 inhibitor that binds to a conserved region within the serine protease domains of MASP-2 and MASP-3.
69 . The pharmaceutical composition of claim 67 , wherein the MASP-3 inhibitory agent is a bispecific monoclonal antibody that binds to the serine protease domain of MASP-3 (aa450-711 of SEQ ID NO:8) and also binds to at least one of the serine protease domain of MASP-2 (aa 445-682 of SEQ ID NO:5) or the CCP-1-CCP2 domain of MASP-2 (aa300-431 of SEQ ID NO:5).
70 . The pharmaceutical composition of claim 47 , wherein the MASP-3 inhibitory agent is a pan inhibitor of MASP-1, MASP-2 and MASP-3 and binds to a conserved region in the CUB 1-EGF-CUB2 domains of the three proteins.
71 . The pharmaceutical composition of claim 47 , wherein the MASP-3 inhibitory agent is a trispecific inhibitor of MASP-1, MASP-2 and MASP-3.
72 . The pharmaceutical composition of claim 47 , wherein the MASP-3 inhibitory agent is a MASP-3 antibody, and wherein the composition further comprises a MASP-2 antibody.
73 . The pharmaceutical composition of claim 47 , wherein the MASP-3 inhibitory agent is a MASP-3 antibody, and wherein the composition further comprises a MASP-1 antibody.
74 . The pharmaceutical composition of claim 47 , wherein the MASP-3 inhibitory agent is a MASP-3 antibody, and wherein the composition further comprises a MASP-2 antibody.
75 . The pharmaceutical composition of claim 47 , wherein the composition comprises a MASP-1 antibody, and MASP-2 antibody and a MASP-3 antibody.
76 . The pharmaceutical composition of claim 57 , wherein the composition further comprises a MASP-2 antibody.
77 . The pharmaceutical composition of claim 61 , wherein the composition further comprises a MASP-3 antibody.
78 . The pharmaceutical composition of claim 67 , wherein the composition further comprises a MASP-1 antibody.
79 . The pharmaceutical composition of claim 47 , wherein the antibody or fragment thereof is selected from the group consisting of a recombinant antibody, an antibody having reduced effector function, a chimeric, and a humanized or human antibody.
80 . The pharmaceutical composition of claim 47 , wherein the MASP-1 inhibitory agent inhibits factor D maturation 81. The pharmaceutical composition of claim 47 , wherein the composition is formulated for systemic delivery.
82 . The pharmaceutical composition of claim 81 , wherein the composition is formulated for delivery subcutaneously, intra-muscularly, intravenously, intra-arterially or as an inhalant.
83 . A pharmaceutical composition comprising a MASP-3 inhibitory agent that binds to a portion of MASP-1 (SEQ ID NO: 10: full-length) and that also binds to a portion of MASP-3 (SEQ ID NO:8) and a pharmaceutical carrier.
84 . The composition of claim 83 , wherein the MASP-3 inhibitory agent is a dual MASP-1/MASP-3 inhibitor.
85 . The composition of claim 83 , wherein the MASP-3 inhibitory agent is a bispecific antibody.
86 . The composition of claim 85 , wherein the MASP-3 inhibitory agent is a bispecific monoclonal antibody that binds to the serine protease domain of MASP-1 (aa 449-694 of SEQ ID NO:10) and also binds to the serine protease domain of MASP-3 (aa 450-711 of SEQ ID NO:8).
87 . A pharmaceutical composition comprising a MASP-3 inhibitory agent that binds to a portion of MASP-2 (SEQ ID NO: 5: full-length) and that also binds to a portion of MASP-3 (SEQ ID NO:8) and a pharmaceutical carrier.
88 . The composition of claim 87 , wherein the MASP-3 inhibitory agent is a dual MASP-2/MASP-3 inhibitor.
89 . The composition of claim 87 , wherein the MASP-3 inhibitory agent is a bispecific MASP-2/MASP-3 antibody.
90 . A pharmaceutical composition comprising a MASP-3 inhibitory agent that binds to a portion of MASP-1 (SEQ ID NO: 10 full length), that binds to a portion of MASP-2 (SEQ ID NO: 5: full-length) and that also binds to a portion of MASP-3 (SEQ ID NO:8) and a pharmaceutical carrier.
91 . The composition of claim 90 , wherein the inhibitory agent is a pan-MASP inhibitor.
92 . The composition of claim 90 , wherein the inhibitory agent is a trispecific MASP-1, MASP-2 and MASP-3 antibody.