Antibody specific for GPC3 and methods of use thereof
The present disclosure provides antibodies specific for glypican-3 (GPC3). Nucleic acids that encode one or both of the variable chain polypeptides 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 useful in various diagnostic, and monitoring applications, which are also provided.
1 . An antibody that specifically binds to Glypican-3 (GPC3), the antibody comprising:
a variable heavy chain (V H ) polypeptide comprising:
a V H CDR1 comprising the amino acid sequence GYTFTSYFLH (SEQ ID NO:2),
a V H CDR2 comprising the amino acid sequence IIDPPTGRTTYAQKFQG (SEQ ID NO:4), and
a V H CDR3 comprising the amino acid sequence GNYGGRYFDY (SEQ ID NO:5); and
a variable light chain (V L ) polypeptide comprising:
a V L CDR1 comprising the amino acid sequence RASQSISSYLN (SEQ ID NO:6),
a V L CDR2 comprising the amino acid sequence AASSLQS (SEQ ID NO:7), and
a V L CDR3 comprising the amino acid sequence QQSYSTPLT (SEQ ID NO:8).
2 . The antibody of claim 1 , wherein the V H polypeptide comprises an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO:9.
3 . The antibody of claim 2 , wherein the V L polypeptide comprises an amino acid sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO:10.
4 . The antibody of claim 1 , wherein the antibody is a humanized antibody.
5 . The antibody of claim 1 , wherein the antibody is a chimeric antibody.
6 . The antibody of claim 1 , wherein the antibody is selected from the group consisting of: an IgG, Fv, single chain antibody, scFv, Fab, F(ab′)2, or Fab′.
7 . The antibody of claim 1 , wherein the antibody is an IgG.
8 . The antibody of claim 7 , wherein the antibody is an IgG1.
9 . The antibody of claim 1 , wherein the antibody is a Fab.
10 . The antibody of claim 1 , wherein the antibody is a single chain antibody.
11 . The antibody of claim 10 , wherein the antibody is an scFv.
12 . The antibody of claim 1 , wherein the antibody is a bispecific antibody comprising a first antigen-binding domain that specifically binds GPC3, and wherein the first antigen binding domain comprises the V H polypeptide and the V L polypeptide as defined in claim 1 .
13 . The antibody of claim 1 , wherein the antibody is detectably labeled.
14 . The antibody of claim 1 , wherein the antibody comprises a covalently linked non-peptide synthetic polymer.
15 . The antibody of claim 14 , wherein the synthetic polymer is poly(ethylene glycol) polymer.
16 . The antibody of claim 1 , wherein the antibody comprises a covalently linked lipid or fatty acid moiety.
17 . The antibody of claim 1 , wherein the antibody comprises a covalently linked polysaccharide or carbohydrate moiety.
18 . The antibody of claim 1 , wherein the antibody comprises a contrast agent.
19 . The antibody of claim 1 , wherein the antibody comprises an affinity domain.
20 . The antibody of claim 1 , wherein the antibody is immobilized on a solid support.
21 . The antibody of claim 1 , wherein the antibody comprises a covalently linked cytotoxin.
22 . The antibody of claim 1 , wherein the antibody comprises a constant region amino acid sequence comprising an amino acid sequence of a sulfatase motif.
23 . The antibody of claim 1 , wherein the antibody comprises a constant region amino acid sequence comprising an amino acid sequence of a sulfatase motif, and wherein the sulfatase motif is modified to comprise a 2-formylglycine (FGly) moiety.
24 . The antibody of claim 23 , wherein the antibody comprises a heterologous moiety covalently linked to the antibody via the FGly moiety.
25 . The antibody of claim 24 , wherein the heterologous moiety is selected from a drug, a toxin, a detectable label, a water-soluble polymer, and a synthetic peptide.
26 . A conjugate, comprising:
the antibody of claim 1 ; and
an agent conjugated to the antibody.
27 . The conjugate of claim 26 , wherein the agent is selected from the group consisting of: a half-life extending moiety, a labeling agent, and a therapeutic agent.
28 . A fusion protein, comprising:
the V H polypeptide, and the V L -polypeptide, of the antibody of claim 1 fused to a heterologous amino acid sequence.
29 . A pharmaceutical composition comprising:
a) the antibody of claim 1 ; and
b) a pharmaceutically acceptable carrier.
30 . A pharmaceutical composition comprising:
a) the conjugate of claim 26 ; and
b) a pharmaceutically acceptable carrier.
31 . A pharmaceutical composition comprising:
a) the fusion protein of claim 28 ; and
b) a pharmaceutically acceptable carrier.
32 . The pharmaceutical composition of claim 29 , further comprising a T cell activator.
33 . The pharmaceutical composition of claim 32 , wherein the T cell activator is selected from the group consisting of: an immune checkpoint inhibitor, a cytokine, and an antagonist of an inhibitory immune receptor.
34 . The pharmaceutical composition of claim 29 , wherein the antibody is encapsulated in a liposome.
35 . A method of treating a cell proliferative disorder in a subject having the cell proliferative disorder, the method comprising:
administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 29 ,
wherein the cell proliferative disorder is associated with or caused by a GPC3-positive cell.
36 . The method of claim 35 , wherein the cell proliferative disorder is a cancer and the GPC3-positive cell is a cancerous GPC3-positive cell.
37 . The method of claim 35 , wherein the GPC3-positive cell is an autoreactive GPC3-positive cell.