# US 10,946,095 B2 · Antibodies specific to human T-cell immunoglobulin and ITIM domain (TIGIT)

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- Number: US 10,946,095 B2
- Document ID: US10946095B2
- Status: Granted
- Kind: B2
- Application number: 15/756,606
- Filed: 2016-09-01
- Published: 2018-07-05
- Granted: 2021-03-16
- Earliest claimed: 2015-09-02
- Assignees: Yissum Research Development Company of the Hebrew University of Jerusalem; University of Rijeka Faculty of Medicine
- Applicants: Yissum Research Development Company of the Hebrew University of Jerusalem Ltd.; University of Rijeka Faculty of Medicine
- Inventors: Ofer Mandelboim; Noa S. Kaynan; Pinchas Tsukerman; Stipan Jonjic
- Web page: https://patentgrep.com/patent/US10946095B2

## CPC

- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61P 35/00: Antineoplastic agents
- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- C07K 16/2803: {against the immunoglobulin superfamily}
- G01N 33/577: involving monoclonal antibodies {binding reaction mechanisms characterised by the use of monoclonal antibodies (G01N33/5302 - G01N33/576 take precedence)}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C12N 5/10: Cells modified by introduction of foreign genetic material
- C12N 15/00: Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor (mutants or genetically engineered microorganisms, per se C12N1/00, C12N5/00, C12N7/00; new plants per se A01H; plant reproduction by tissue culture techniques A01H4/00; new animals per se A01K67/00; use of medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases, gene therapy A61K48/00)
- C12N 15/63: Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Monoclonal antibodies that recognize TIGIT and inhibit its suppressive activity on T-cells are provided as well as pharmaceutical compositions including them and methods for their use in cancer immunotherapy and in diagnosis and treatment of immune disorders.

## Claims

### Claim 1

An isolated monoclonal antibody which binds to human T-cell immunoglobulin and ITIM domain (TIGIT), or an antibody fragment thereof comprising at least the antigen binding portion of the monoclonal antibody, wherein the isolated antibody or antibody fragment is selected from the group consisting of:
(i) an isolated antibody or antibody fragment thereof comprising six complementarity determining regions (CDRs), wherein the heavy chain (HC) CDR1 comprises the sequence GYTFTSYGIS (SEQ ID NO:1) or TSYGIS (SEQ ID NO:11); the HC CDR2 comprises the sequence: EIYPRSGNTYYNEKFKG (SEQ ID NO:2); the HC CDR3 comprises the sequence: KGPYYTKNEDY (SEQ ID NO:3); the light chain (LC) CDR1 comprises the sequence: RASEHIYYSLA (SEQ ID NO:4); the LC CDR2 comprises the sequence: NANSLED (SEQ ID NO:5); and the LC CDR3 comprises the sequence: KQAYDVPRT (SEQ ID NO: 6); and
(ii) an isolated antibody or antibody fragment thereof comprising six CDRs, wherein the HC CDR1 comprises the sequence IYCIH (SEQ ID NO:12); the HC CDR2 comprises the sequence: EISPSNGRTIYNEKFKN (SEQ ID NO:13); the HC CDR3 comprises the sequence: SDGYDGYYFDY (SEQ ID NO:14); LC CDR1 comprises the sequence: RASQEISGYLN (SEQ ID NO:15); the LC CDR2 comprises the sequence: AASTLDS (SEQ ID NO:16); and the LC CDR3 comprises the sequence: LQYASYPRT (SEQ ID NO:17).

### Claim 2 (depends on 1)

The isolated monoclonal antibody or the antibody fragment according to claim 1, comprising a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO:7 and the light chain comprises SEQ ID NO:8.

### Claim 3 (depends on 1)

The isolated monoclonal antibody or the antibody fragment according to claim 1, comprising a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO:18 and the light chain comprises SEQ ID NO:19.

### Claim 4 (depends on 1)

The isolated monoclonal antibody of claim 1 wherein the antibody is selected from the group consisting of: a bispecific antibody, a humanized antibody, and an antibody conjugate.

### Claim 5 (depends on 4)

The isolated monoclonal antibody of claim 4, wherein the bispecific antibody comprises two sets of CDR sequences, wherein:
one CDR set comprises an HC CDR1 having the sequence GYTFTSYGIS (SEQ ID NO:1) or TSYGIS (SEQ ID NO: 11); an HC CDR2 having the sequence: EIYPRSGNTYYNEKFKG (SEQ ID NO:2); an HC CDR3 having the sequence: KGPYYTKNEDY (SEQ ID NO:3); an LC CDR1 having the sequence: RASEHIYYSLA (SEQ ID NO:4); an LC CDR2 having the sequence: NANSLED (SEQ ID NO:5); and an LC CDR3 having the sequence: KQAYDVPRT (SEQ ID NO:6); and
a second set comprises an HC CDR1 having the sequence: IYCIH (SEQ ID NO:12), an HC CDR2 having the sequence: EISPSNGRTIYNEKFKN (SEC ID NO:13), an HC CDR3 having the sequence: SDGYDGYYFDY (SEC ID NO:14), an LC CDR1 having the sequence: RASQEISGYLN (SEC ID NO: 15), an LCCDR2 having the sequence: AASTLDS (SEQ ID NO: 16), and an LC CDR3 having the sequence: LQYASYPRT (SEC ID NO:17).

### Claim 6 (depends on 1)

The isolated monoclonal antibody according to claim 1 capable of inhibiting binding of TIGIT to at least one ligand selected from the group consisting of PVR (CD155), PVRL2 (CD112), PVRL3 (CD113), and any combination thereof.

### Claim 7 (depends on 1)

The monoclonal antibody according to claim 1 attached to a cytotoxic moiety, a radioactive moiety, or an identifiable moiety.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising as an active ingredient, at least one isolated antibody or fragment thereof according to claim 1, and a pharmaceutical acceptable excipient, diluent, salt, or carrier.

### Claim 9 (depends on 8)

A method of treating cancer, comprising administering to a subject in need thereof, a pharmaceutical composition according to claim 8.

### Claim 10 (depends on 9)

The method of claim 9 further comprising administering an additional anti-cancer therapy selected from surgery, chemotherapy, radiotherapy, and immunotherapy.

### Claim 11 (depends on 10)

The method of claim 10, wherein the immunotherapy comprising administering an antibody that binds an immune checkpoint molecule selected from the group consisting of PD-1, CTLA-4, PDL-1, CEACAM1, lymphocyte activation gene 3 (LAG3), CD137, OX40 (also referred to as CD134), killer cell immunoglobulin-like receptors (KIR), and any combination thereof.

### Claim 12 (depends on 10)

The method of claim 10 wherein the immunotherapy comprises administration of an antibody that inhibits epidermal growth factor receptor (EGFR).

### Claim 13 (depends on 1)

A kit for measuring the expression of TIGIT in biological sample comprising at least one antibody or antibody fragment according to claim 1.