Anti-LAG-3 antibody and use thereof

Patent metadata

Field	Value
Publication number	US-11655295-B2
Application number	US-201916963067-A
Country	US
Kind code	B2
Filing date	Jan 3, 2019
Priority date	Jan 18, 2018
Publication date	May 23, 2023
Grant date	May 23, 2023

Abstract

The present invention relates to the field of treatment of diseases and immunology. Specifically, the present invention relates to an anti-LAG-3 antibody or an antigen-binding fragment thereof, nucleic acid molecules for encoding said antibody and fragment, and method for preparing said antibody and fragment. The anti-LAG-3 antibody or the antigen-binding fragment thereof according to the present invention has high specificity and high affinity to LAG-3, can effectively block the binding of LAG-3 to MHC II and/or FGL1, and can inhibit and/or block intracellular signaling mediated by LAG-3 binding to MHC II and/or FGL1. Therefore, the present invention further relates to a pharmaceutical composition comprising the antibody or the antigen-binding fragment thereof, and use of the pharmaceutical composition in the preparation of drugs. The drugs are used for improving the activity of immune cells and enhancing the immune response, or are used for preventing and/or treating tumors, infections or autoimmune diseases.

First claim

What is claimed:

1. An antibody or antigen-binding fragment thereof which is capable of specifically binding to LAG-3, comprising:
(1) three CDRs of the heavy chain variable region (VII) as shown in SEQ ID NO: 1;
and three CDRs of the light chain variable region (VL) as shown in SEQ ID NO: 2;
(2) three CDRs of the heavy chain variable region (VII) as shown in SEQ ID NO: 16;
and three CDRs of the light chain variable region (VL) as shown in SEQ ID NO: 17;
(3) three CDRs of the heavy chain variable region (VII) as shown in SEQ ID NO: 18;
and three CDRs of the light chain variable region (VL) as shown in SEQ ID NO: 19;
(4) three CDRs of the heavy chain variable region (VII) as shown in SEQ ID NO: 20;
and three CDRs of the light chain variable region (VL) as shown in SEQ ID NO: 21;
(5) three CDRs of the heavy chain variable region (VII) as shown in SEQ ID NO: 22;
and three CDRs of the light chain variable region (VL) as shown in SEQ ID NO: 23;
(6) three CDRs of the heavy chain variable region (VII) as shown in SEQ ID NO: 24;
and three CDRs of the light chain variable region (VL) as shown in SEQ ID NO: 25; or
(7) three CDRs of the heavy chain variable region (VII) as shown in SEQ ID NO: 26;
and three CDRs of the light chain variable region (VL) as shown in SEQ ID NO: 27;
wherein, the three CDRs of the heavy chain variable region (VII) and the three CDRs of the light chain variable region (VL) are defined by the Kabat, Chothia or IMGT numbering system.

2. The antibody or an antigen-binding fragment thereof according to claim 1 , wherein:
(1) the antibody or an antigen-binding fragment comprises the following six CDRs defined in accordance with the IMGT numbering system: VH CDR1 as set forth in SEQ ID NO: 3; VH CDR2 as set forth in SEQ ID NO: 4; VH CDR3 as set forth in SEQ ID NO: 5; VLCDR1 as set forth in SEQ ID NO: 6; VL CDR2 as set forth in SEQ ID NO: 7; and VL CDR3 as set forth in SEQ ID NO: 8;
or
(2) the antibody or an antigen-binding fragment comprises the following six CDRs defined in accordance with the Chothia numbering system:
(2a) VH CDR1 as set forth in SEQ ID NO: 9; VH CDR2 as set forth in SEQ ID NO: 10; VH CDR3 as set forth in SEQ ID NO: 11; VL CDR1 as set forth in SEQ ID NO: 12; VL CDR2 as set forth in SEQ ID NO: 13; and VL CDR3 as set forth in SEQ ID NO: 8; or,
(2b) VH CDR1 as set forth in SEQ ID NO: 9; VH CDR2 as set forth in SEQ ID NO: 10; VHCDR3 as set forth in SEQ ID NO: 11; VL CDR1 as set forth in SEQ ID NO: 12; VL CDR2 as set forth in SEQ ID NO: 54; and VL CDR3 as set forth in SEQ ID NO: 8;
or
(3) the antibody or an antigen-binding fragment comprises the following six CDRs defined in accordance with the Kabat numbering system:
(3a) VH CDR1 as set forth in SEQ ID NO: 14; VH CDR2 as set forth in SEQ ID NO: 15; VH CDR3 as set forth in SEQ ID NO: 11; VLCDR1 as set forth in SEQ ID NO: 12; VL CDR2 as set forth in SEQ ID NO: 13; and VL CDR3 as set forth in SEQ ID NO: 8; or,
(3b) VH CDR1 as set forth in SEQ ID NO: 14; VH CDR2 as set forth in SEQ ID NO: 55; VH CDR3 as set forth in SEQ ID NO: 11; VLCDR1 as set forth in SEQ ID NO: 12; VL CDR2 as set forth in SEQ ID NO: 13; and VL CDR3 as set forth in SEQ ID NO: 8; or,
(3c) VH CDR1 as set forth in SEQ ID NO: 56; VH CDR2 as set forth in SEQ ID NO: 57; VH CDR3 as set forth in SEQ ID NO: 11; VLCDR1 as set forth in SEQ ID NO: 12; VL CDR2 as set forth in SEQ ID NO: 54; and VL CDR3 as set forth in SEQ ID NO: 8; or,
(3d) VH CDR1 as set forth in SEQ ID NO: 14; VH CDR2 as set forth in SEQ ID NO: 58; VH CDR3 as set forth in SEQ ID NO: 11; VL CDR1 as set forth in SEQ ID NO: 12; VL CDR2 as set forth in SEQ ID NO: 13; and VL CDR3 as set forth in SEQ ID NO: 8.

3. The antibody or an antigen-binding fragment thereof according to claim 1 , wherein, the antibody or an antigen-binding fragment thereof comprises:
(1) VH as set forth in SEQ ID NO: 1, and VL as set forth in SEQ ID NO: 2;
(2) VH as set forth in SEQ ID NO: 16, and VL as set forth in SEQ ID NO: 17;
(3) VH as set forth in SEQ ID NO: 18, and VL as set forth in SEQ ID NO: 19;
(4) VH as set forth in SEQ ID NO: 20, and VL as set forth in SEQ ID NO: 21;
(5) VH as set forth in SEQ ID NO: 22, and VL as set forth in SEQ ID NO: 23;
(6) VH as set forth in SEQ ID NO: 24, and VL as set forth in SEQ ID NO: 25; or
(7) VH as set forth in SEQ ID NO: 26, and VL as set forth in SEQ ID NO: 27.

4. The antibody or an antigen-binding fragment thereof according to claim 1 , wherein,
the antibody or an antigen-binding fragment further comprises: (a) a heavy chain constant region (CH) of a human immunoglobulin or a variant thereof, wherein the variant is described below, and (b) a light chain constant region (CL) of a human immunoglobulin;
wherein the variant of heavy chain constant region (CH) is selected from the following:
(1) a variant of human IgG1 heavy chain constant region, wherein the variant comprises the following substitutions: Leu234Ala, Leu235Ala and Gly237Ala, compared to the wild-type sequence from which it is derived;
(2) a variant of human IgG1 heavy chain constant region, wherein the variant comprises the following substitutions: Asn297Ala, Asp356Glu and Leu358Met, compared to the wild-type sequence from which it is derived;
(3) a variant of human IgG4 heavy chain constant region, wherein the variant comprises the following substitution: Ser228Pro, compared to the wild-type sequence from which it is derived;
wherein the amino acid positions mentioned above are based on EU numbering system.

5. The antibody or an antigen-binding fragment thereof according to claim 1 , wherein, the antibody or an antigen-binding fragment thereof is a chimeric antibody or a humanized antibody.

6. The antibody or an antigen-binding fragment thereof according to claim 1 , wherein, the antibody or an antigen-binding fragment thereof comprises:
(1) a heavy chain having a sequence as set forth in SEQ ID NO: 38, and a light chain having a sequence as set forth in SEQ ID NO: 39;
(2) a heavy chain having a sequence as set forth in SEQ ID NO: 40, and a light chain having a sequence as set forth in SEQ ID NO: 41;
(3) a heavy chain having a sequence as set forth in SEQ ID NO: 42, and a light chain having a sequence as set forth in SEQ ID NO: 43;
(4) a heavy chain having a sequence as set forth in SEQ ID NO: 44, and a light chain having a sequence as set forth in SEQ ID NO: 45;
(5) a heavy chain having a sequence as set forth in SEQ ID NO: 46, and a light chain having a sequence as set forth in SEQ ID NO: 47;
(6) a heavy chain having a sequence as set forth in SEQ ID NO: 48, and a light chain having a sequence as set forth in SEQ ID NO: 49;
(7) a heavy chain having a sequence as set forth in SEQ ID NO: 50, and a light chain having a sequence as set forth in SEQ ID NO: 51; or
(8) a heavy chain having a sequence as set forth in SEQ ID NO: 52, and a light chain having a sequence as set forth in SEQ ID NO: 53.

7. The antibody or an antigen-binding fragment thereof according to claim 1 , wherein, the antibody or an antigen-binding fragment thereof is selected from scFv, Fab, Fab′, F(ab′) 2 , Fv fragment, disulfide bond ligated Fv (dsFv), diabody, bispecific antibody and multi-specific antibody.

8. An isolated nucleic acid molecule, encoding an antibody or antigen-binding fragment thereof according to claim 1 , or a heavy chain variable region and a light chain variable region thereof.

9. The isolated nucleic acid molecule of claim 8 , comprising a nucleic acid molecule encoding an antibody heavy chain variable region, and a nucleic acid molecule encoding an antibody light chain variable region, wherein,
the nucleic acid molecule encoding an antibody heavy chain variable region has a sequence selected from:
(a) a nucleic

Assignees

• Sichuan Kelun Biotech Biopharmaceutical Co Ltd

Inventors

• Xue Tongtong
• Li Qiang
• Xiao Liang
• Zheng Yuncheng
• Liu Dengnian
• Chen Si
• Hu Yan
• Wang Lichun
• Wang Jingyi

Classifications

• A61K39/39558

  against tumor tissues, cells, antigens · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07K2317/24

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title