ANTIBODY SPECIFIC FOR MUCIN-1 AND METHODS OF USE THEREOF
The present disclosure provides antibodies specific for Mucin 1. Nucleic acids that encode one or both of the variable chains of an antibody of the present disclosure are also provided, as are cells that include such nucleic acids. Also provided are compositions that include the antibodies of the present disclosure, including in some instances, pharmaceutical compositions. Methods of making and using the antibodies of the present disclosure are also provided. In certain aspects, provided are methods that include administering to an individual having a cell proliferative disorder a therapeutically effective amount of an antibody of the present disclosure, where the antibody is administered to the individual to enhance an immune response, e.g., a T cell response, to abnormally proliferating cells of the cell proliferative disorder. The antibodies are also useful in various diagnostic, and monitoring applications, which are also provided.
1 . (canceled)
2 . A nucleic acid encoding a heavy chain variable domain (VH), a light chain variable domain (VL), or both, of an antibody that specifically binds to Mucin-1 (MUC-1),
wherein the VH comprises a heavy chain complementarity determining region 1 (HCDR1), a heavy chain complementarity determining region 2 (HCDR2), and a heavy chain complementarity determining region 3 (HCDR3) as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 1, and
wherein the VL comprises a light chain complementarity determining region 1 (LCDR1), a light chain complementarity determining region 2 (LCDR2), and a light chain complementarity determining region 3 (LCDR3) as set forth in a VL comprising the amino acid sequence of any one of SEQ ID NOs: 2, 3, or 4.
3 . The nucleic acid according to claim 2 , wherein the VH comprises:
an HCDR1 comprising the amino acid sequence DHTMH (SEQ ID NO: 17);
an HCDR2 comprising the amino acid sequence YFYPRDDSTNYNEKFKG (SEQ ID NO: 18); and
an HCDR3 comprising the amino acid sequence GLRYALDY (SEQ ID NO: 9); and
the VL comprises:
a) an LCDR1 comprising the amino acid sequence RASSSVSSSYLY (SEQ ID NO: 10),
an LCDR2 comprising the amino acid sequence GTSNLAS (SEQ ID NO: 11), and
an LCDR3 comprising the amino acid sequence HQYAWSPPT (SEQ ID NO: 12); or
b) an LCDR1 comprising the amino acid sequence RASSSVGSSNLY (SEQ ID NO: 13),
an LCDR2 comprising the amino acid sequence RSTKLAS (SEQ ID NO: 14), and
an LCDR3 comprising the amino acid sequence HQYRWSPPT (SEQ ID NO: 15); or
c) an LCDR1 comprising the amino acid sequence RASSSVSSSYLY (SEQ ID NO: 10),
an LCDR2 comprising the amino acid sequence GTSNLAS (SEQ ID NO: 11), and
an LCDR3 comprising the amino acid sequence HQYSWSPPT (SEQ ID NO: 16).
4 . The nucleic acid according to claim 2 , wherein the VH comprises an amino acid sequence having at least 80% identity to the amino acid sequence set forth in SEQ ID NO: 1.
5 . The nucleic acid according to claim 4 , wherein the VL comprises an amino acid sequence having at least 80% identity to the amino acid sequence set forth in any one of SEQ ID NO: 2, 3, or 4.
6 . The nucleic acid according to claim 2 , wherein the antibody comprises:
(i) HCDR1 comprising the amino acid sequence DHTMH (SEQ ID NO: 17),
an HCDR2 comprising the amino acid sequence YFYPRDDSTNYNEKFKG (SEQ ID NO: 18),
an HCDR3 comprising the amino acid sequence GLRYALDY (SEQ ID NO: 9),
an LCDR1 comprising the amino acid sequence RASSSVSSSYLY (SEQ ID NO: 10),
an LCDR2 comprising the amino acid sequence GTSNLAS (SEQ ID NO: 11), and
an LCDR3 comprising the amino acid sequence HQYAWSPPT (SEQ ID NO: 12), as per Kabat definition; or
(ii) an HCDR1 comprising the amino acid sequence GYTFTDH (SEQ ID NO: 7),
an HCDR2 comprising the amino acid sequence YPRDDS (SEQ ID NO: 8),
an HCDR3 comprising the amino acid sequence GLRYALDY (SEQ ID NO: 9),
an LCDR1 comprising the amino acid sequence RASSSVSSSYLY (SEQ ID NO: 10),
an LCDR2 comprising the amino acid sequence GTSNLAS (SEQ ID NO: 11), and
an LCDR3 comprising the amino acid sequence HQYAWSPPT (SEQ ID NO: 12), as per Chothia definition; or
(iii) an HCDR1 comprising the amino acid sequence GYTFTDHT (SEQ ID NO: 34),
an HCDR2 comprising the amino acid sequence FYPRDDST (SEQ ID NO: 44),
an HCDR3 comprising the amino acid sequence ARGLRYALDY (SEQ ID NO: 45),
an LCDR1 comprising the amino acid sequence SSVSSSY (SEQ ID NO: 33),
an LCDR2 comprising the amino acid sequence GT, and
an LCDR3 comprising the amino acid sequence HQYAWSPPT (SEQ ID NO: 12), as per IMGT definition.
7 . The nucleic acid according to claim 2 , wherein the antibody comprises:
(i) an HCDR1 comprising the amino acid sequence DHTMH (SEQ ID NO: 17), an HCDR2 comprising the amino acid sequence YFYPRDDSTNYNEKFKG (SEQ ID NO: 18),
an HCDR3 comprising the amino acid sequence GLRYALDY (SEQ ID NO: 9),
an LCDR1 comprising the amino acid sequence RASSSVGSSNLY (SEQ ID NO: 13),
an LCDR2 comprising the amino acid sequence RSTKLAS (SEQ ID NO: 14), and
an LCDR3 comprising the amino acid sequence HQYRWSPPT (SEQ ID NO: 15), as per Kabat definition, or
(ii) an HCDR1 comprising the amino acid sequence GYTFTDH (SEQ ID NO: 7),
an HCDR2 comprising the amino acid sequence YPRDDS (SEQ ID NO: 8),
an HCDR3 comprising the amino acid sequence GLRYALDY (SEQ ID NO: 9),
an LCDR1 comprising the amino acid sequence RASSSVGSSNLY (SEQ ID NO: 13),
an LCDR2 comprising the amino acid sequence RSTKLAS (SEQ ID NO: 14), and
an LCDR3 comprising the amino acid sequence HQYRWSPPT (SEQ ID NO: 15), as per Chothia definition; or
(iii) an HCDR1 comprising the amino acid sequence GYTFTDHT (SEQ ID NO: 34),
an HCDR2 comprising the amino acid sequence FYPRDDST (SEQ ID NO: 44),
an HCDR3 comprising the amino acid sequence ARGLRYALDY (SEQ ID NO: 45),
an LCDR1 comprising the amino acid sequence SSVGSSN (SEQ ID NO: 46),
an LCDR2 comprising the amino acid sequence RS, and
an LCDR3 comprising the amino acid sequence HQYRWSPPT (SEQ ID NO: 15), as per IMGT definition.
8 . The nucleic acid according to claim 2 , wherein the antibody comprises:
(i) an HCDR1 comprising the amino acid sequence DHTMH (SEQ ID NO: 17),
an HCDR2 comprising the amino acid sequence YFYPRDDSTNYNEKFKG (SEQ ID NO: 18);
an HCDR3 comprising the amino acid sequence GLRYALDY (SEQ ID NO: 9),
an LCDR1 comprising the amino acid sequence RASSSVSSSYLY (SEQ ID NO: 10),
an LCDR2 comprising the amino acid sequence GTSNLAS (SEQ ID NO: 11), and
an LCDR3 comprising the amino acid sequence HQYSWSPPT (SEQ ID NO: 16), as per Kabat definition or
(ii) an HCDR1 comprising the amino acid sequence GYTFTDH (SEQ ID NO: 7),
an HCDR2 comprising the amino acid sequence YPRDDS (SEQ ID NO: 8),
an HCDR3 comprising the amino acid sequence GLRYALDY (SEQ ID NO: 9),
an LCDR1 comprising the amino acid sequence RASSSVSSSYLY (SEQ ID NO: 10),
an LCDR2 comprising the amino acid sequence GTSNLAS (SEQ ID NO: 11), and
an LCDR3 comprising the amino acid sequence HQYSWSPPT (SEQ ID NO: 16), as per Chothia definition; or
(iii) an HCDR1 comprising the amino acid sequence GYTFTDHT (SEQ ID NO: 34),
an HCDR2 comprising the amino acid sequence FYPRDDST (SEQ ID NO: 44),
an HCDR3 comprising the amino acid sequence ARGLRYALDY (SEQ ID NO: 45),
an LCDR1 comprising the amino acid sequence SSVSSSY (SEQ ID NO: 33),
an LCDR2 comprising the amino acid sequence GT, and
an LCDR3 comprising the amino acid sequence HQYSWSPPT (SEQ ID NO: 16), as per IMGT definition.
9 . The nucleic acid according to claim 2 , wherein the antibody is a humanized antibody or a chimeric antibody.
10 . The nucleic acid according to claim 2 , wherein the antibody is selected from the group consisting of: an IgG, Fv, single chain antibody, scFv, Fab, F(ab′)2, or Fab′.
11 . The nucleic acid according to claim 10 , wherein the antibody is an IgG1 or a bispecific antibody.
12 . The nucleic acid according to claim 2 , wherein the antibody comprises a constant region comprising an amino acid sequence of a sulfatase motif.
13 . The nucleic acid according to claim 2 , wherein the VH comprises the amino acid sequence as set forth in SEQ ID NO: 1, and wherein the VL comprises the amino acid sequence as set forth in any one of SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.
14 . The nucleic acid according to claim 2 , comprising a nucleic acid sequence as set forth in SEQ ID NO: 19 or a nucleic acid sequence having at least 80% sequence identity thereto.
15 . The nucleic acid according to claim 14 , comprising a nucleic acid sequence as set forth in any one of SEQ ID NOs: 38, 39, or 40, or a nucleic acid sequence having at least 80% sequence identity of each thereto.
16 . The nucleic acid according to claim 15 , wherein the antibody or fragment thereof comprises a constant region comprising an amino acid sequence of a sulfatase motif.
17 . The nucleic acid according to claim 2 , wherein the antibody is a single chain antibody, and wherein the nucleic acid encodes the single chain antibody.
18 . The nucleic acid of claim 18 , wherein the single chain antibody is an scFv.
19 . A recombinant expression vector comprising the nucleic acid of claim 2 , wherein the nucleic acid is operably linked to a transcriptional control element that is active in a eukaryotic cell.
20 . A cell comprising the nucleic acid of claims 2 .
21 . A cell comprising the expression vector of claim 19 .
22 . A cell comprising:
a first nucleic acid encoding a VH of an antibody that specifically binds to MUC-1, wherein the VH comprises an HCDR1, an HCDR2, and an HCDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 1; and
a second nucleic acid encoding a VL of the antibody, wherein the VL comprises a LCDR1, a LCDR2, and a LCDR3 as set forth in a VL comprising the amino acid sequence of any one of SEQ ID NOs: 2, 3, or 4.
23 . The cell according to claim 22 , comprising:
a first nucleic acid comprising a nucleic acid sequence as set forth in SEQ ID NO: 19 or a nucleic acid sequence having at least 80% sequence identity thereto; and
a second nucleic acid comprising a nucleic acid sequence as set forth in any one of SEQ ID NOs: 38, 39, or 40, or a nucleic acid sequence having at least 80% sequence identity of each thereto.
24 . The cell according to claim 22 , comprising:
a first expression vector comprising the first nucleic acid; and
a second expression vector comprising the second nucleic acid.
25 . A fusion protein, comprising:
a VH, a VL, or both, of an antibody that specifically binds to MUC-1; fused to
a heterologous amino acid sequence,
wherein the VH comprises an HCDR1, an HCDR2, and an HCDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO: 1, and
wherein the VL comprises a LCDR1, a LCDR2, and a LCDR3 as set forth in a VL comprising the amino acid sequence of any one of SEQ ID NOs: 2, 3, or 4.