MASP-2 AND MASP-3 INHIBITORS, AND RELATED COMPOSITIONS AND METHODS, FOR TREATMENT OF SICKLE CELL DISEASE
The present disclosure relates to the use of MASP-2 inhibitors and/or MASP-3 inhibitors and compositions comprising the same for treatment of sickle cell disease, including treatment, reduction, and/or prevention of sickle cell disease symptoms or manifestations.
1 . A method of treating sickle cell disease, the method comprising administering to a mammalian subject in need thereof a therapeutically effective amount of:
i. a MASP-2 inhibitor;
ii. a MASP-3 inhibitor; or
iii. a MASP-2 inhibitor and a MASP-3 inhibitor.
2 . The method of claim 1 , wherein the MASP-2 inhibitor inhibits lectin pathway complement activation in the subject.
3 . The method of claim 1 , wherein the MASP-3 inhibitor inhibits alternative pathway complement activation in the subject.
4 . The method of claim 1 , wherein the MASP-2 inhibitor is an antibody or antigen-binding fragment thereof.
5 . The method of claim 1 , wherein the MASP-3 inhibitor is an antibody or antigen-binding fragment thereof.
6 . The method of claim 1 , wherein the MASP-2 inhibitor and/or MASP-3 inhibitor is an antibody or antigen-binding fragment thereof selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, a murine antibody, and an antigen-binding fragment of any of the foregoing.
7 . The method of claim 1 , wherein the MASP-2 inhibitor and/or MASP-3 inhibitor is an antibody or antigen-binding fragment thereof is selected from the group consisting of a single chain antibody, an ScFv, a Fab fragment, an Fab′ fragment, an F(ab′)2 fragment, a univalent antibody lacking a hinge region and a whole antibody.
8 . (canceled)
9 . (canceled)
10 . The method of claim 5 , wherein the MASP-3 inhibitor is an antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising a HC-CDR1 set forth as SEQ ID NO:12, a HC-CDR2 set forth as SEQ ID NO:13, and a HC-CDR3 set forth as SEQ ID NO:14; and a light chain variable region comprising a LC-CDR1 set forth as SEQ ID NO:16, a LC-CDR2 set forth as SEQ ID NO:17, and a LC-CDR3 set forth as SEQ ID NO:18.
11 . The method of claim 10 , wherein the antibody or antigen-binding fragment thereof comprises a VH comprising a sequence at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:11 and a VL comprising a sequence at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:15.
12 . The method of claim 4 , wherein the MASP-2 inhibitor is an antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising a HC-CDR1 set forth as SEQ ID NO:4, a HC-CDR2 set forth as SEQ ID NO:5, and a HC-CDR3 set forth as SEQ ID NO:6; and a light chain variable region comprising a LC-CDR1 set forth as SEQ ID NO:8, a LC-CDR2 set forth as SEQ ID NO:9, and a LC-CDR3 set forth as SEQ ID NO:10.
13 . The method of claim 12 , wherein the antibody or antigen-binding fragment thereof comprises a VH comprising a sequence at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:3 and a VL comprising a sequence at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:7.
14 . The method of claim 12 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising a sequence at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:1 and a VL comprising a sequence at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:7.
15 . The method of claim 4 , wherein the antibody or antigen-binding fragment comprises a fusion protein comprising a VH, an IgG constant region, and an inhibitory peptide.
16 . The method of claim 15 , wherein the inhibitory peptide comprises the sequence set forth as SEQ ID NO:2.
17 . The method of claim 16 , wherein the fusion protein comprises a sequence at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:1.
18 . The method of claim 4 wherein the MASP-2 inhibitor is an antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising a HC-CDR1 set forth as SEQ ID NO:34, a HC-CDR2 set forth as SEQ ID NO:21, and a HC-CDR3 set forth as SEQ ID NO:22; and a light chain variable region comprising a LC-CDR1 set forth as SEQ ID NO:24, a LC-CDR2 set forth as SEQ ID NO:25, and a LC-CDR3 set forth as SEQ ID NO:26.
19 . The method of claim 18 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising a sequence at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:33 and a VL comprising a sequence at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:23.
20 . The method of claim 4 wherein the MASP-2 inhibitor is an antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising a HC-CDR1 set forth as SEQ ID NO:20, a HC-CDR2 set forth as SEQ ID NO:21, and a HC-CDR3 set forth as SEQ ID NO:22; and a light chain variable region comprising a LC-CDR1 set forth as SEQ ID NO:24, a LC-CDR2 set forth as SEQ ID NO:25, and a LC-CDR3 set forth as SEQ ID NO:26.
21 . The method of claim 20 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising a sequence at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:19 and a VL comprising a sequence at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:23.
22 . The method of claim 4 wherein the MASP-2 inhibitor is an antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising a HC-CDR1 set forth as SEQ ID NO:28, a HC-CDR2 set forth as SEQ ID NO:29, and a HC-CDR3 set forth as SEQ ID NO:22; and a light chain variable region comprising a LC-CDR1 set forth as SEQ ID NO:24, a LC-CDR2 set forth as SEQ ID NO:25, and a LC-CDR3 set forth as SEQ ID NO:26.
23 . The method of claim 22 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising a sequence at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:27 and a VL comprising a sequence at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:30.
24 . The method of claim 4 wherein the MASP-2 inhibitor is an antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising a HC-CDR1 set forth as SEQ ID NO:28, a HC-CDR2 set forth as SEQ ID NO:29, and a HC-CDR3 set forth as SEQ ID NO:22; and a light chain variable region comprising a LC-CDR1 set forth as SEQ ID NO:24, a LC-CDR2 set forth as SEQ ID NO:25, and a LC-CDR3 set forth as SEQ ID NO:26.
25 . The method of claim 24 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising a sequence at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:31 and a VL comprising a sequence at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:23.
26 . The method of claim 4 wherein the MASP-2 inhibitor is an antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising a HC-CDR1 set forth as SEQ ID NO:28, a HC-CDR2 set forth as SEQ ID NO:21, and a HC-CDR3 set forth as SEQ ID NO:22; and a light chain variable region comprising a LC-CDR1 set forth as SEQ ID NO:24, a LC-CDR2 set forth as SEQ ID NO:25, and a LC-CDR3 set forth as SEQ ID NO:26.
27 . The method of claim 26 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising a sequence at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:32 and a VL comprising a sequence at least 80%, 85%, 90%, 95%, 98%, 99% or 100% identical to SEQ ID NO:23.
28 . A method of treating, reducing, and/or preventing vaso-occlusion associated with sickle cell disease, the method comprising administering to a mammalian subject in need thereof a therapeutically effective amount of:
i. a MASP-2 inhibitor;
ii. a MASP-3 inhibitor; or
iii. a MASP-2 inhibitor and a MASP-3 inhibitor.
29 - 54 . (canceled)
55 . A method of treating, reducing, and/or preventing inflammation associated with sickle cell disease, the method comprising administering to a mammalian subject in need thereof a therapeutically effective amount of:
i. a MASP-2 inhibitor;
ii. a MASP-3 inhibitor; or
iii. a MASP-2 inhibitor and a MASP-3 inhibitor.
56 - 80 . (canceled)
81 . A method of treating, preventing, and/or reducing the number, duration, and/or severity of crisis episodes associated with sickle cell disease, the method comprising administering to a mammalian subject in need thereof a therapeutically effective amount of:
i. a MASP-2 inhibitor;
ii. a MASP-3 inhibitor; or
iii. a MASP-2 inhibitor and a MASP-3 inhibitor.
82 - 107 . (canceled)
108 . A method of treating, preventing, and/or reducing pain associated with sickle cell disease, the method comprising administering to a mammalian subject in need thereof a therapeutically effective amount of:
i. a MASP-2 inhibitor;
ii. a MASP-3 inhibitor; or
iii. a MASP-2 inhibitor and a MASP-3 inhibitor.
109 - 134 . (canceled)
135 . A composition comprising a MASP-3 and/or MASP-2 inhibitor for use in treating sickle cell disease.
136 . A composition comprising a MASP-3 and/or MASP-2 inhibitor for use in treating, reducing, and/or preventing vaso-occlusion associated with sickle cell disease.
137 . A composition comprising a MASP-3 and/or MASP-2 inhibitor for use in treating, reducing, and/or preventing inflammation associated with sickle cell disease.
138 . A composition comprising a MASP-3 and/or MASP-2 inhibitor for use in treating, preventing, and/or reducing the number, duration, and/or severity of crisis episodes associated with sickle cell disease.
139 . A composition comprising a MASP-3 and/or MASP-2 inhibitor for use in treating, preventing, and/or reducing pain associated with sickle cell disease.
140 . The composition of claim 135 , further comprising a pharmaceutically acceptable excipient.
141 . (canceled)