ANTI-TIM-3 ANTIBODY

• US 20140044728A1
• Filed: 09/05/2013
• Published: 02/13/2014
• Est. Priority Date: 06/11/2010
• Status: Active Grant

• Current Assignee: Kyowa Kirin Co., Ltd. (Kirin Holdings Company Limited)
• Original Assignee: Kyowa Hakko Kirin Company Limited (Kirin Holdings Company Limited), Kyushu University
• Inventors: TAKAYANAGI, Shin-ichiro, TAWARA, Tomonori, INAGAKI, Yoshimasa, KUBOTA, Tsuguo, KIKUSHIGE, Yoshikane, TOMURA, Hitomi, AKASHI, Koichi
• Granted Patent: US 9,556,270 B2
• Time in Patent Office: Days
• US Class Current: 424/154.1
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: C07K 16/2803 : against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2818 : against CD28 or CD152
• CPC Class Codes: C07K 2317/14 : Specific host cells or culture conditions, e.g. components, pH or temperature
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/33 : Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/34 : Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/732 : Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: G01N 33/56972 : White blood cells

Abstract

Disclosed are an anti-human TIM-3 antibody having high ADCC activity or antibody fragment thereof by screening a monoclonal antibody or antibody fragment thereof which binds to the amino acid sequence of the extracellular region of TIM-3 or its three-dimensional structure and exhibits ADCC activity; a hybridoma which produces the antibody; a DNA encoding the antibody; a vector comprising the DNA; a transformant which is obtainable by introducing the vector; a method for producing the antibody or the antibody fragment thereof which comprises using the hybridoma or the transformant; and a therapeutic agent and a diagnostic agent comprising the antibody or the antibody fragment thereof as an active ingredient.

Claims

1. A monoclonal antibody or an antigen-binding fragment, which binds to an extracellular region of human T-cell immunoglobulin and mucin domain containing molecule-3 (TIM-3) while competing with one antibody selected from the following (a) to (c):

(a) an antibody or an antigen-binding fragment thereof, each comprising a heavy chain (H chain) and a light chain (L chain), wherein complementarity determining regions (CDRs) 1 to 3 of said H chain comprises the amino acid sequences of SEQ ID NOs;

1 to 3, respectively, and CDRs 1 to 3 of said L chain comprises the amino acid sequences of SEQ ID NOs;

4 to 6, respectively,

(b) an antibody or an antigen-binding fragment thereof, each comprising an H chain and L chain, wherein CDRs 1 to 3 of said H chain comprises the amino acid sequences of SEQ ID NOs;

11 to 13, respectively, and CDRs 1 to 3 of said L chain comprises the amino acid sequences of SEQ ID NOs;

14 to 16, respectively, and

(c) an antibody or an antigen-binding fragment thereof, each comprising an H chain and L chain, wherein CDRs 1 to 3 of said H chain comprises the amino acid sequences of SEQ ID NOs;

21 to 23, respectively, and CDRs 1 to 3 of said L chain comprises the amino acid sequences of SEQ ID NOs;

24 to 26, respectively.

2. The monoclonal antibody or the antigen-binding fragment thereof according to claim 1, which binds to the same epitope as an epitope to which one antibody selected from the above (a) to (c) binds.

3. The monoclonal antibody or the antigen-binding fragment thereof according to claim 1, which is a recombinant antibody.

4. The monoclonal antibody or the antigen-binding fragment thereof according to claim 3, which is a recombinant antibody selected from a human chimeric antibody, a humanized antibody and a human antibody.

5. The monoclonal antibody or the antigen-binding fragment thereof according to claim 1, which binds to the amino acid residues at positions 67 to 105, the amino acid residues at positions 67 to 96 or the amino acid residues at positions 67 to 87 in the amino acid sequence of IgV domain of human T-cell immunoglobulin and mucin domain containing molecule-3 (TIM-3) of SEQ ID NO:

53.

6. The antigen-binding fragment according to claim 1, which is selected from the group consisting of a Fab, a Fab′

, a F(ab′

)₂, a single chain antibody (scFv), a dimerized V region (diabody), a disulfide stabilized V region (dsFv) and a peptide comprising CDR.

7. A process for producing a monoclonal antibody or an antigen-binding fragment thereof that binds to an extracellular region of human T-cell immunoglobulin and mucin domain containing molecule-3 (TIM-3), said process comprising culturing a transformant comprising a DNA encoding the monoclonal antibody or the antigen binding fragment thereof according to claim 1 in a culture medium to form and accumulate the monoclonal antibody or the antigen binding fragment thereof, and recovering the monoclonal antibody or the antigen-binding fragment thereof from the culture.

8. A method for immunologically detecting or measuring human T-cell immunoglobulin and mucin domain containing molecule-3 (TIM-3), which comprises using the monoclonal antibody or the antigen-binding fragment thereof according to claim 1.

9. A method for diagnosing a disease relating to a human T-cell immunoglobulin and mucin domain containing molecule-3 (TIM-3) positive cell, which comprises detecting or measuring a human TIM-3 positive cell or human TIM-3, using the monoclonal antibody or the antigen-binding fragment thereof according to claim 1.

10. A pharmaceutical composition, comprising the monoclonal antibody or the antigen-binding fragment thereof according to claim 1 and a pharmaceutically acceptable carrier.

17. A process for producing a monoclonal antibody or an antigen-binding fragment thereof that binds to an extracellular region of human T-cell immunoglobulin and mucin domain containing molecule-3 (TIM-3), said process comprising culturing a transformant comprising a DNA encoding the monoclonal antibody or the antigen binding fragment thereof according to claim 1 in a culture medium to form and accumulate the monoclonal antibody or the antigen binding fragment thereof, and recovering the monoclonal antibody or the antigen-binding fragment thereof from the culture.

11. A monoclonal antibody or an antigen-binding fragment, which binds to an extracellular region of human T-cell immunoglobulin and mucin domain containing molecule-3 (TIM-3) while competing with one antibody selected from the following (a) and (b):

(a) an antibody or an antigen-binding fragment thereof, each comprising an H chain variable region (VH) and a L chain variable region (VL), wherein said VH and VL comprises the amino acid sequences of SEQ ID NO;

8 and SEQ ID NO;

10, respectively, and

(b) an antibody or an antigen-binding fragment thereof, each comprising VH and VL comprises the amino acid sequences of SEQ ID NO;

18 and SEQ ID NO;

20, respectively.

12. The monoclonal antibody or the antigen-binding fragment thereof according to claim 11, which binds to the same epitope as an epitope to which one antibody selected from the above (a) and (b) binds.

13. The monoclonal antibody or the antigen-binding fragment thereof according to claim 11, which is a recombinant antibody.

14. The monoclonal antibody or the antigen-binding fragment thereof according to claim 13, which is a recombinant antibody selected from a human chimeric antibody, a humanized antibody and a human antibody.

15. The monoclonal antibody or the antigen-binding fragment thereof according to claim 11, which binds to the amino acid residues at positions 67 to 105, the amino acid residues at positions 67 to 96 or the amino acid residues at positions 67 to 87 in the amino acid sequence of IgV domain of human T-cell immunoglobulin and mucin domain containing molecule-3 (TIM-3) of SEQ ID NO:

53.

16. The antigen-binding fragment according to claim 11, which is selected from the group consisting of a Fab, a Fab′

, a F(ab′

)₂, a single chain antibody (scFv), a dimerized V region (diabody), a disulfide stabilized V region (dsFv) and a peptide comprising CDR.

18. A method for immunologically detecting or measuring human T-cell immunoglobulin and mucin domain containing molecule-3 (TIM-3), which comprises using the monoclonal antibody or the antigen-binding fragment thereof according to claim 11.

19. A method for diagnosing a disease relating to a human T-cell immunoglobulin and mucin domain containing molecule-3 (TIM-3) positive cell, which comprises detecting or measuring a human TIM-3 positive cell or human TIM-3, using the monoclonal antibody or the antigen-binding fragment thereof according to claim 11.

20. A pharmaceutical composition, comprising the monoclonal antibody or the antigen-binding fragment thereof according to claim 11 and a pharmaceutically acceptable carrier.