Antibodies to galectin-3 and methods of use thereof
Provided herein are compositions, methods, and uses involving antibodies that specifically bind the Galectin-3 (LGALS3) carbohydrate binding domain (CBD). Also provided herein are uses and methods for managing, treating, or preventing disorders, such as cancer.
1 . An antibody or an antigen-binding fragment thereof that specifically binds to a Galectin-3 (LGALS3),
wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (V H ) and a light chain variable region (V L ), wherein:
(a) the V H comprises a V H complementarity determining region (CDR)1 sequence comprising SEQ ID NO: 7, a V H CDR2 sequence comprising SEQ ID NO: 8, and a V H CDR3 sequence comprising SEQ ID NO: 9, and the V L comprises a V L CDR1 sequence comprising SEQ ID NO: 2, a V L CDR2 sequence comprising SEQ ID NO: 3, and a V L CDR3 sequence comprising SEQ ID NO: 4;
(b) the V H comprises a V H complementarity determining region (CDR)1 sequence comprising SEQ ID NO: 19, a V H CDR2 sequence comprising SEQ ID NO: 20, and a V H CDR3 sequence comprising SEQ ID NO: 21, and the V L comprises a V L CDR1 sequence comprising SEQ ID NO: 14, a V L CDR2 sequence comprising SEQ ID NO: 15, and a V L CDR3 sequence comprising SEQ ID NO: 16;
(c) the V H comprises a V H complementarity determining region (CDR)1 sequence comprising SEQ ID NO: 29, a V H CDR2 sequence comprising SEQ ID NO: 30, and a V H CDR3 sequence comprising SEQ ID NO: 31, and the V L comprises a V L CDR1 sequence comprising SEQ ID NO: 24, a V L CDR2 sequence comprising SEQ ID NO: 25, and a V L CDR3 sequence comprising SEQ ID NO: 26;
(d) the V H comprises a V H complementarity determining region (CDR)1 sequence comprising SEQ ID NO: 39, a V H CDR2 sequence comprising SEQ ID NO: 40, and a V H CDR3 sequence comprising SEQ ID NO: 41, and the V L comprises a V L CDR1 sequence comprising SEQ ID NO: 34, a V L CDR2 sequence comprising SEQ ID NO: 35, and a V L CDR3 sequence comprising SEQ ID NO: 36; or
(e) the V H comprises a V H complementarity determining region (CDR)1 sequence comprising SEQ ID NO: 49, a V H CDR2 sequence comprising SEQ ID NO: 50, and a V H CDR3 sequence comprising SEQ ID NO: 51, and the V L comprises a V L CDR1 sequence comprising SEQ ID NO: 44, a V L CDR2 sequence comprising SEQ ID NO: 45, and a V L CDR3 sequence comprising SEQ ID NO: 46,
optionally wherein
the antibody or antigen-binding fragment is generated by immunizing a transgenic mouse; or
the antibody is a monoclonal antibody; or
the antigen-binding fragment is a Fab, F(ab′) 2 , Fab′, Fv or scFv.
2 . The antibody or antigen-binding fragment of claim 1 , wherein the V H comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 18, SEQ ID NO: 28, SEQ ID NO: 38, and SEQ ID NO: 48 or
wherein the V L comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 13, SEQ ID NO: 23, SEQ ID NO: 33, and SEQ ID NO: 43.
3 . A polynucleotide comprising nucleic acid sequences encoding the antibody or antigen-binding fragment of claim 2 .
4 . The polynucleotide of claim 3 , wherein the polynucleotide comprises the polynucleotide of any one of SEQ ID NO: 5, SEQ ID NO: 17, SEQ ID NO: 27, SEQ ID NO: 37, SEQ ID NO: 47, SEQ ID NO: 10, SEQ ID NO: 22, SEQ ID NO: 32, SEQ ID NO: 42, or SEQ ID NO: 52.
5 . A vector comprising the polynucleotide of claim 3 , optionally wherein the polynucleotide is operably linked to a promoter.
6 . An isolated cell comprising the polynucleotide of claim 3 or a vector comprising the polynucleotide.
7 . The antibody or antigen-binding fragment of claim 1 , comprising a V H amino acid sequence and a V L amino acid sequence selected from the group consisting of SEQ ID NO: 6 and SEQ ID NO: 1, SEQ ID NO: 18 and SEQ ID NO: 13, SEQ ID NO: 28 and SEQ ID NO: 23, SEQ ID NO: 38 and SEQ ID NO: 33, and SEQ ID NO: 48 and SEQ ID NO: 43, respectively.
8 . The antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a human or humanized heavy chain variable domain (V H ) and/or a human or humanized a light chain variable domain (V L ); or wherein the antibody or antigen-binding fragment is a humanized or fully human antibody or antigen-binding fragment thereof.
9 . The antibody or antigen-binding fragment of claim 1 , wherein the antibody comprises human-derived heavy and light chain constant regions, optionally wherein the heavy chain constant region has an isotype selected from the group consisting of gamma 1, gamma 2, gamma 3, and gamma 4; or wherein the light chain constant region has an isotype selected from the group consisting of kappa and lambda.
10 . The antibody or antigen-binding fragment of claim 1 , wherein the antibody is an immunoglobulin comprising two identical heavy chains and two identical light chains, optionally wherein the immunoglobulin is an IgG; or
wherein the antibody or antigen-binding fragment inhibits Gal-3-Phycoerythrin (PE) binding to ovarian tumor cells, optionally wherein the ovarian tumor cells are OVCAR3 cells; or
wherein the antibody or antigen-binding fragment thereof inhibits binding of LGALS3 to a glycosylated cell surface receptor; or
wherein the antibody or antigen-binding fragment inhibits binding of LGALS3 to a glycosylated growth factor receptor; or
wherein the antibody or antigen-binding fragment inhibits binding of LGALS3 to one or more of glycosylated mucin-1 (MUC1), mucin-4 (MUC4), mucin-16 (MUC16), a disialoganglioside, GD2, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), insulin-like growth factor receptor (IGFR), an integrin or CTLA4, optionally wherein the glycosylated MUC16 is N-glycosylated at Asn1800 or Asn1806; or
wherein the antibody or antigen-binding fragment inhibits growth of a tumor that expresses a glycosylated form of MUC16.
11 . An antibody conjugate comprising the antibody or antigen-binding fragment of claim 1 conjugated to an agent, optionally wherein the agent is an imaging agent or a cytotoxic agent.
12 . The antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment is a bispecific antibody, optionally wherein the bispecific antibody specifically binds CD3 or wherein the bispecific antibody comprises an immunoglobulin that specifically binds LGALS3, wherein the light chain of the immunoglobulin is conjugated via a peptide linker to a single chain variable fragment (scFv) that specifically binds to CD3.
13 . A bispecific antibody conjugate comprising the bispecific antibody of claim 12 conjugated to an agent, optionally wherein the agent is an imaging agent or a cytotoxic agent.
14 . An scFv conjugate comprising an scFv of the antigen binding fragment of claim 1 conjugated to an agent, optionally wherein the agent is an imaging agent or a cytotoxic agent.
15 . A chimeric antigen receptor (CAR) comprising: the antibody or antigen-binding fragment of claim 1 , optionally wherein the antigen-binding fragment is a scFv.
16 . A T-cell that recombinantly expresses the CAR of claim 15 .
17 . A pharmaceutical composition comprising: a therapeutically effective amount of the antibody or antigen-binding fragment of claim 1 ; and a pharmaceutically acceptable carrier.
18 . A method of treating cancer in a patient in need thereof, comprising administering to said patient an effective amount of the pharmaceutical composition of claim 17 , optionally wherein the pharmaceutical composition inhibits metastasis in the patient.
19 . The method of claim 18 , wherein said cancer is a cancer of the ovary, lung, pancreas, breast, uterine, fallopian tube, or primary peritoneum or wherein said cancer is a metastatic cancer.
20 . The method of claim 18 , wherein the method further comprises administering a therapeutically effective amount of an additional therapeutic agent to the patient.