Glypican-3 (GPC-3) antibodies

Patent metadata

Field	Value
Publication number	US-12404341-B2
Application number	US-202017441519-A
Country	US
Kind code	B2
Filing date	Mar 22, 2020
Priority date	Mar 21, 2019
Publication date	Sep 2, 2025
Grant date	Sep 2, 2025

Abstract

We describe an antibody or antigen-binding fragment thereof comprising a heavy chain variable region (V H ) sequence and a light chain variable region (V L ) sequence of a clone selected from: 5C4, 4H1, 1D2, 1C4, 2B5, 1F1, 1H1, 4A5, 1D8, 1D3, 2F1, 3C6, 3D12, 3A9, 1F4, 1H10, 3C12, 4G11, 4A12, 1A12, 3G12, 4F9, 4G4 and 1E1 which is capable of specifically binding to glypican-3 (GPC-3) (GenBank Accession Number: NP_004475.1), or a sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity thereto.

First claim

The invention claimed is:

1. An antibody or antigen-binding fragment thereof comprising a heavy chain variable region (V H ) sequence and a light chain variable region (V L ) sequence of a clone selected from: 5C4, 4H1, 1D2, 1C4, 2B5, 1F1, 1H1, 4A5, 1D8, 1D3, 2F1, 3C6, 3D12, 3A9, 1F4, 1H10, 3C12, 4G11, 4A12, 1A12, 3G12, 4F9, 4G4 and 1E1 and which specifically binds to glypican-3 (GPC-3).

2. The antibody or antigen-binding fragment according to claim 1 , in which the V H and V L sequence are selected from: SEQ ID NO: 1 and SEQ ID NO: 2; SEQ ID NO: 3 and SEQ ID NO: 4; SEQ ID NO: 5 and SEQ ID NO: 6; SEQ ID NO: 7 and SEQ ID NO: 8; SEQ ID NO: 9 and SEQ ID NO: 10; SEQ ID NO: 11 and SEQ ID NO: 12; SEQ ID NO: 13 and SEQ ID NO: 14; SEQ ID NO: 15 and SEQ ID NO: 16; SEQ ID NO: 17 and SEQ ID NO: 18; SEQ ID NO: 19 and SEQ ID NO: 20; SEQ ID NO: 21 and SEQ ID NO: 22; SEQ ID NO: 23 and SEQ ID NO: 24; SEQ ID NO: 25 and SEQ ID NO: 26; SEQ ID NO: 27 and SEQ ID NO: 28; SEQ ID NO: 29 and SEQ ID NO: 30; SEQ ID NO: 31 and SEQ ID NO: 32; SEQ ID NO: 33 and SEQ ID NO: 34; SEQ ID NO: 35 and SEQ ID NO: 36; SEQ ID NO: 37 and SEQ ID NO: 38; SEQ ID NO: 39 and SEQ ID NO: 40; SEQ ID NO: 41 and SEQ ID NO: 42; SEQ ID NO: 43 and SEQ ID NO: 44; SEQ ID NO: 45 and SEQ ID NO: 46; and SEQ ID NO: 47 and SEQ ID NO: 48.

3. The antibody or antigen-binding fragment according to claim 1 , which binds to an epitope of human glypican-3 (GPC-3) with an affinity of 55 nM or less, 50 nM or less, 45 nM or less, 40 nM or less, 35 nM or less, nM or less, 25 nM or less, 20 nM or less, 15 nM or less, 10 nM or less, 5 nM or less, 1 nM or less, 0.9 nM or less, 0.8 nM or less, 0.7 nM or less, 0.6 nM or less, 0.5 nM or less, 0.4 nM or less, 0.3 nM or less, 0.2 nM or less or 0.1 nM or less, measured as a EC50 as determined by ELISA.

4. The antibody or antigen-binding fragment according to claim 1 , which binds to a cell line selected from the group consisting of: GPC-3 High HepG2 cells; and GPC-3 Medium Hep3B cells.

5. The antibody or antigen-binding fragment according to claim 1 , which is capable of inducing Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) of a GPC-3 expressing cell in the presence of natural killer (NK) cells, wherein the antibody or antigen-binding fragment comprises a heavy variable chain region (V H ) sequence and a light chain variable region (V L ) sequence of a clone selected from the group consisting of 1C4 (SEQ ID NOs: 7 and 8, respectively), 1D2 (SEQ ID NOs: 5 and 6, respectively), 1D3 (SEQ ID NOs: 19 and 20, respectively), 1D8 (SEQ ID NOs: 17 and 18, respectively), 1E1 (SEQ ID NOS: 47 and 48, respectively), 1H1 (SEQ ID NOs: 13 and 14, respectively), 1H10 (SEQ ID NOs: 31 and 32, respectively), 2B5 (SEQ ID NOs: 9 and 10, respectively), 2F1 (SEQ ID NOs: 21 and 22, respectively), 3A9 (SEQ ID NOs: 27 and 28, respectively), 3C12 (SEQ ID NOs: 33 and 34, respectively), 3G12 (SEQ ID NOs: 41 and 42, respectively), 4A5 (SEQ ID NOs: 15 and 16, respectively), 4A12 (SEQ ID NOs: 37 and 38, respectively), 4F9 (SEQ ID NOs: 43 and 44, respectively), 4G4 (SEQ ID NOs: 45 and 46, respectively), 4H1 (SEQ ID NOs: 3 and 4, respectively), and 5C4 (SEQ ID Nos: 1 and 2, respectively).

6. The antibody or antigen-binding fragment according claim 1 , which is a humanised antibody comprising a human constant region.

7. The antibody or antigen-binding fragment according to claim 1 , which comprises a monoclonal antibody, a humanised monoclonal antibody, an Fv, F(ab′), F(ab′) 2 or single-chain Fv (scFv) fragment.

8. The antibody or antigen-binding fragment according claim 1 , which further comprises a heavy chain variable region (V H ) sequence and a light chain variable region (V L ) that binds to CD3.

9. The antibody or antigen-binding fragment according to claim 8 , in which the heavy chain variable region (V H ) sequence and a light chain variable region (V L ) sequence that bind to CD3 comprise the sequences set out in SEQ ID NO: 97 and SEQ ID NO: 98.

10. The antibody or antigen-binding fragment according to claim 8 , which activates T-cells.

11. A chimeric antigen receptor (CAR) comprising: (a) the antigen-binding fragment according to claim 1 ; (b) a transmembrane domain; and (c) a co-stimulatory intracellular signalling domain; or a chimeric antigen receptor T Cell (CAR T) expressing said chimeric antigen receptor.

12. A nucleic acid that encodes an antibody or antigen-binding fragment according claim 1 , comprising sequences selected from the group consisting of: SEQ ID NO: 49 and SEQ ID NO: 50; SEQ ID NO: 51 and SEQ ID NO: 52; SEQ ID NO: 53 and SEQ ID NO: 54; SEQ ID NO: 55 and SEQ ID NO: 56; SEQ ID NO: 57 and SEQ ID NO: 58; SEQ ID NO: 59 and SEQ ID NO: 60; SEQ ID NO: 61 and SEQ ID NO: 62; SEQ ID NO: 63 and SEQ ID NO: 64; SEQ ID NO: 65 and SEQ ID NO: 66; SEQ ID NO: 67 and SEQ ID NO: 68; SEQ ID NO: 69 and SEQ ID NO: 70; SEQ ID NO: 71 and SEQ ID NO: 72; SEQ ID NO: 73 and SEQ ID NO: 74; SEQ ID NO: 75 and SEQ ID NO: 76; SEQ ID NO: 77 and SEQ ID NO: 78; SEQ ID NO: 79 and SEQ ID NO: 80; SEQ ID NO: 81 and SEQ ID NO: 82; SEQ ID NO: 83 and SEQ ID NO: 84; SEQ ID NO: 85 and SEQ ID NO: 86; SEQ ID NO: 87 and SEQ ID NO: 88; SEQ ID NO: 89 and SEQ ID NO: 90; SEQ ID NO: 91 and SEQ ID NO: 92; SEQ ID NO: 93 and SEQ ID NO: 94; and SEQ ID NO: 95 and SEQ ID NO: 96.

13. A host cell comprising the nucleic acid according to claim 12 , in which the host cell comprises a Chinese Hamster Ovary (CHO) or a HEK293 cell.

14. A pharmaceutical composition comprising:
(a) an antibody or antigen-binding fragment thereof comprising a heavy chain variable region (V H ) sequence and a light chain variable region (V L ) sequence of a clone selected from: 5C4, 4H1, 1D2, 1C4, 2B5, 1F1, 1H1, 4A5, 1D8, 1D3, 2F1, 3C6, 3D12, 3A9, 1F4, 1H10, 3C12, 4G11, 4A12, 1A12, 3G12, 4F9, 4G4 and 1E1 and which specifically binds to glypican-3 (GPC-3); or
(b) a CAR comprising: (i) the antigen-binding fragment according to (a); (ii) a transmembrane domain; and (iii) a co-stimulatory intracellular signalling domain; or a CAR T expressing said CAR; or
(c) a nucleic acid that encodes the antibody or antigen-binding fragment of (a), comprising sequences selected from the group consisting of: SEQ ID NO: 49 and SEQ ID NO: 50; SEQ ID NO: 51 and SEQ ID NO: 52; SEQ ID NO: 53 and SEQ ID NO: 54; SEQ ID NO: 55 and SEQ ID NO: 56; SEQ ID NO: 57 and SEQ ID NO: 58; SEQ ID NO: 59 and SEQ ID NO: 60; SEQ ID NO: 61 and SEQ ID NO: 62; SEQ ID NO: 63 and SEQ ID NO: 64; SEQ ID NO: 65 and SEQ ID NO: 66; SEQ ID NO: 67 and SEQ ID NO: 68; SEQ ID NO: 69 and SEQ ID NO: 70; SEQ ID NO: 71 and SEQ ID NO: 72; SEQ ID NO: 73 and SEQ ID NO: 74; SEQ ID NO: 75 and SEQ ID NO: 76; SEQ ID NO: 77 and SEQ ID NO: 78; SEQ ID NO: 79 and SEQ ID NO: 80; SEQ ID NO: 81 and SEQ ID NO: 82; SEQ ID NO: 83 and SEQ ID NO: 84; SEQ ID NO: 85 and SEQ ID NO: 86; SEQ ID NO: 87 and SEQ ID NO: 88; SEQ ID NO: 89 and SEQ ID NO: 90; SEQ ID NO: 91 and SEQ ID NO: 92; SEQ ID NO: 93 and SEQ ID NO: 94; and SEQ ID NO: 95 and SEQ ID NO: 96.

15. A compound comprising the antibody or antigen-binding fragment thereof according to claim 1 linked to a cytotoxic agent.

16. The compound according to claim 15 , in which the compound comprises an antibody-drug conjugate.

17. A method of producing an antibody or antigen-binding fragment, the method comprising expressing the nucleic acid according to claim 12 in a host cell.

18. A method of detecting a hepatocellular carcinoma (HCC) cell, the method comprising detecting modulation of expression, amount or activity of glypican-3 (GPC-3) in or of the cell, by means of the antibody or antigen-binding fragment according t

Assignees

• Agency Science Tech & Res

Inventors

• Wang Cheng-I
• Wang Bei
• Ngoh Zi Xian Eve
• Lee Wen-Hsin
• Huang Ching-Wen
• Yeap Yee Chin Yvonne

Classifications

• G01N33/57525

  of the liver or pancreas · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K2317/622

  Single chain antibody (scFv) · CPC title

• C07K2317/56

  variable (Fv) region, i.e. VH and/or VL · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title