Antibodies binding LAG3 and methods of treatment using them
An isolated monoclonal antibody or an antigen-binding portion thereof that specifically binds human LAG3. A nucleic acid molecule encoding the antibody or antigen-binding portion thereof, an expression vector, a host cell and a method for expressing the antibody or antigen-binding portion thereof are also provided. The present disclosure further provides an immuneconjugate, a bispecific molecule, a chimeric antigen receptor, and a pharmaceutical composition comprising the antibody or antigen-binding portion thereof thereof, as well as a treatment method using the same.
1. An isolated monoclonal antibody, or an antigen-binding portion thereof, binding to LAG3, comprising a heavy chain variable region comprising a V H CDR1 region, a V H CDR2 region and a V H CDR3 region, and a light chain variable region comprising a V L CDR1 region, a V L CDR2 region and a V L CDR3 region, wherein the V H CDR1 region, the V H CDR2 region, the V H CDR3 region, the V L CDR1 region, the V L CDR2 region and the V L CDR3 region comprise the amino acid sequences set forth in (1) SEQ ID NOs: 1, 2, 3, 5, 6 and 7, respectively; (2) SEQ ID NOs: 1, 2, 4, 5, 6 and 8, respectively; or (3) SEQ ID NOs: 21, 22, 23, 24, 25 and 26, respectively.
2. The antibody, or the antigen-binding portion thereof, according to claim 1 , wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NOs: 9, 10, 11, 12, 13, 14, 27, 28, 29 or 30.
3. The antibody, or the antigen-binding portion thereof, according to claim 1 , wherein the light chain variable region comprises the amino acid sequence set forth in SEQ ID NOs: 15, 16, 17, 18, 19, 20, 31, 32, 33 or 34.
4. The antibody, or the antigen-binding portion thereof, according to claim 2 , wherein the heavy chain variable region and the light chain variable region comprise the amino acid sequences set forth in (1) SEQ ID NOs: 9 and 15, respectively; (2) SEQ ID NOs: 10 and 16, respectively; (3) SEQ ID NOs: 11 and 17, respectively; (4) SEQ ID NOs: 11 and 19, respectively; (5) SEQ ID NOs: 12 and 17, respectively; (6) SEQ ID NOs: 12 and 19, respectively; (7) SEQ ID NOs: 13 and 18, respectively; (8) SEQ ID NOs: 13 and 20, respectively; (9) SEQ ID NOs: 14 and 20, respectively; (10) SEQ ID NOs: 27 and 31, respectively; (11) SEQ ID NOs: 28 and 32, respectively; (12) SEQ ID NOs: 29 and 33, respectively; (13) SEQ ID NOs: 29 and 34, respectively; (14) SEQ ID NOs: 30 and 33, respectively; or (15) SEQ ID NOs: 30 and 34, respectively.
5. The antibody, or the antigen-binding portion thereof, according to claim 1 , comprising a heavy chain constant region which is human IgG1 or IgG4 heavy chain constant region, linked to the heavy chain variable region, and/or a light chain constant region which is human kappa light chain constant region, linked to the light chain variable region.
6. The antibody, or the antigen-binding portion thereof, according to claim 5 , wherein the heavy chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 35, and the light chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 36.
7. The antibody, or the antigen-binding portion thereof, according to claim 1 , which (a) binds human LAG3; (b) binds monkey LAG3; (c) does not bind mouse LAG3; (d) blocks LAG3-MHC II complex interaction; (e) induces T cell activation; and/or (f) provides in vivo anti-tumor effect.
8. The antibody, or the antigen-binding portion thereof, according to claim 1 , which is a mouse, chimeric or humanized antibody.
9. A pharmaceutical composition comprising the antibody, or the antigen-binding portion thereof, according to claim 1 , and a pharmaceutically acceptable carrier.
10. The pharmaceutical composition according to claim 9 , further comprising an anti-tumor agent, an anti-infective agent, or an anti-inflammatory agent.
11. A method for enhancing an immune response in a subject, comprising administering to the subject a therapeutically effect amount of the pharmaceutical composition according to claim 9 , wherein the enhanced immune response is T cell activation or T cell stimulation.
12. The method according to claim 11 , wherein the subject is further administered with an anti-tumor agent, a cytokine and/or a costimulatory antibody.
13. The method according to claim 12 , wherein the anti-tumor agent is anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-STAT3 antibody, an anti-ROR1 antibody, an anti-TIM3 antibody, and/or an anti-CTLA-4 antibody.
14. The method according to claim 12 , wherein the cytokine is IL-2 or IL-21.
15. The method according to claim 12 , wherein the costimulatory antibody is an anti-CD137 or an anti-GITR antibody.
16. A method for treating a solid tumor in a subject in need thereof, comprising administering to the subject a therapeutically effect amount of the pharmaceutical composition according to claim 9 , wherein the solid tumor is colon adenocarcinoma.
17. The method according to claim 16 , wherein the subject is further administered with an anti-tumor agent, a cytokine, and/or a costimulatory antibody.
18. The method according to claim 17 , wherein the anti-tumor agent is anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-STAT3 antibody, an anti-ROR1 antibody, an anti-TIM3 antibody, and/or an anti-CTLA-4 antibody.
19. The method according to claim 17 , wherein the cytokine is IL-2 or IL-21.
20. The method according to claim 17 , wherein the costimulatory antibody is an anti-CD137 or an anti-GITR antibody.