ANTI-STEM CELL FACTOR ANTIBODIES AND METHODS OF BLOCKING THE INTERACTION BETWEEN SCF AND c-KIT
The disclosure relates to antibodies and antigen-binding fragments thereof that bind to Stem Cell Factor (SCF). The antibodies and antigen-binding fragments thereof specifically bind to SCF248. The disclosure further relates to methods for making the antibodies, and to methods of use of the antibodies including methods of treatment for inflammatory and/or fibrotic diseases and disorders.
1 - 5 . (canceled)
6 . A method for treating pulmonary fibrosis in a subject in need of treatment, comprising administering to the subject, an antibody or antigen-binding fragment thereof comprising heavy chain CDR1, CDR2, and CDR3 and light chain CDR1, CDR2, and CDR3, wherein the amino acid sequences of the heavy chain CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 1, 2, and 3, respectively; and the amino acid sequences of the light chain CDR1, CDR2, and CDR3 comprise SEQ ID NOs: 4, 5, and 6, respectively.
7 . The method of claim 6 , wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.
8 . The method of claim 6 , wherein the pulmonary fibrosis is scleroderma lung fibrosis.
9 . The method of claim 6 , wherein the pulmonary fibrosis is scleroderma-related interstitial lung disease.
10 . The method of claim 6 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 8, 9, 10, and 11; and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 13, 14, 15, and 16.
11 . The method of claim 10 , wherein the antibody or antigen-binding fragment thereof comprises:
(a) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 16;
(b) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8 and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 16;
(c) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9 and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 16;
(d) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10 and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 16; or
(e) the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 11 and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 16.
12 . The method of claim 11 , wherein the antibody or antigen-binding fragment thereof comprises the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 8 and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 16.
13 . The method of claim 6 , wherein the antibody or antigen-binding fragment thereof is humanized.
14 . The method of claim 6 , wherein the antibody or antigen-binding fragment thereof is a monoclonal antibody or antigen-binding fragment thereof.
15 . The method of claim 14 , wherein the monoclonal antibody or antigen-binding fragment thereof comprises a human IgG4 domain.
16 . The method of claim 15 , wherein the human IgG4 domain comprises a S241P mutation at amino acid residue 241 and an L248E mutation at amino acid residue 248, wherein the numbering of the residues is that of the Kabat numbering system.
17 . The method of claim 15 , wherein the human IgG4 domain comprises the amino acid sequence of SEQ ID NO: 40.
18 . The method of claim 14 , wherein the monoclonal antibody or antigen-binding fragment thereof is a monoclonal antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 42 and a light chain having the amino acid sequence of SEQ ID NO: 49, or antigen-binding fragment thereof.
19 . The method of claim 14 , wherein the monoclonal antibody or antigen-binding fragment thereof is a monoclonal antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 43 and a light chain having the amino acid sequence of SEQ ID NO: 49, or antigen-binding fragment thereof.
20 . The method of claim 6 , wherein
(a) the antibody or antigen-binding fragment thereof blocks the interaction between SCF and c-Kit;
(b) the antibody or antigen-binding fragment thereof causes internalization of SCF; and/or
(c) the antibody or antigen-binding fragment thereof specifically binds to SCF248 and does not bind to SCF220.
21 . The method of claim 6 , wherein the antibody or antigen-binding fragment thereof binds to an epitope comprising at least 8 contiguous amino acids of SEQ ID NO: 33, wherein the antibody or antigen-binding fragment thereof inhibits the interaction of SCF248 with c-Kit.
22 . The method of claim 21 , wherein the epitope consists of SEQ ID NO: 33.
23 . The method of claim 6 , wherein the antibody or antigen-binding fragment thereof comprises a light chain human Ig kappa constant domain.
24 . The method of claim 23 , wherein the light chain human Ig kappa constant domain comprises the amino acid sequence of SEQ ID NO: 41.
25 . The method of claim 6 , wherein the antibody or antigen-binding fragment thereof comprises a light chain human Ig lambda constant domain.
26 . The method of claim 6 , wherein the antibody or antigen-binding fragment thereof is administered parenterally to the subject.
27 . The method of claim 6 , wherein the antibody or antigen-binding fragment thereof is administered subcutaneously to the subject.
28 . The method of claim 6 , wherein the antibody or antigen-binding fragment thereof is administered intravenously to the subject.
29 . The method of claim 18 , wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.
30 . The method of claim 18 , wherein the pulmonary fibrosis is scleroderma lung fibrosis.
31 . The method of claim 18 , wherein the pulmonary fibrosis is scleroderma-related interstitial lung disease.