# US 10,766,957 B2 · Anti-TIGIT antibodies

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- Number: US 10,766,957 B2
- Document ID: US10766957B2
- Status: Granted
- Kind: B2
- Application number: 15/751,618
- Filed: 2016-08-09
- Published: 2018-12-27
- Granted: 2020-09-08
- Earliest claimed: 2015-08-14
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme Corp.
- Inventors: Sybil M. G. Williams; Wolfgang Seghezzi; Laurence Fayadat-Dilman; Linda Liang; Veronica Juan
- Web page: https://patentgrep.com/patent/US10766957B2

## CPC

- C07K 16/2803: {against the immunoglobulin superfamily}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 39/39566: {against immunoglobulins, e.g. anti-idiotypic antibodies}
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61K 2039/572: {cytotoxic response}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- 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
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- 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
- 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)
- 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
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention relates to anti-TIGIT antibodies, as well as use of these antibodies in the treatment of diseases such as cancer and infectious disease.

## Claims

### Claim 1

An antibody or antigen binding fragment thereof that binds to human T cell immunoreceptor with Ig and ITIM domains (TIGIT), wherein the antibody or antigen binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a heavy chain variable region CDR1, a heavy chain variable region CDR2, and a heavy chain variable region CDR3, and the light chain variable region comprises a light chain variable region CDR1, a light chain variable region CDR2, and a light chain variable region CDR3; and wherein the antibody or antigen binding fragment thereof is selected from the group consisting of:
a. an antibody or antigen binding fragment thereof comprising: a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3, 45, 46, or 47, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:6, 57, 58, 59, 60, 61, or 62; and
b. an antibody or antigen binding fragment thereof comprising: a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:17, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:18, 81, 82, 83, 84, 85, 86, 87, or 88, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:19, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:20, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:22.

### Claim 2 (depends on 1)

The antibody or antigen binding fragment thereof of claim 1, wherein the antibody comprises a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:2, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:3, 45, 46, or 47, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:6, 57, 58, 59, 60, 61, or 62.

### Claim 3 (depends on 1)

The antibody or antigen binding fragment thereof of claim 1, wherein the antibody comprises a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:17, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 18, 81, 82, 83, 84, 85, 86, 87, or 88, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:19, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:20, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:22.

### Claim 4 (depends on 1)

The antibody or antigen binding fragment thereof of claim 1, wherein the antibody binds to human TIGIT with a KD value of about 1×10−9 M to about 1×10−12 M as determined by surface plasmon resonance.

### Claim 5 (depends on 1)

The antibody or antigen binding fragment thereof of claim 1, wherein the antibody is a humanized antibody comprising two heavy chains and two light chains.

### Claim 6 (depends on 5)

The antibody or antigen binding fragment thereof of claim 5, wherein the humanized antibody comprises a human IgG1 constant domain and a human kappa constant domain.

### Claim 7 (depends on 1)

The antibody or antigen binding fragment thereof of claim 1, light chain, wherein the heavy chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 26, 27, and 28, and wherein the light chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 30, 31, and 32.

### Claim 8 (depends on 7)

The antibody or antigen binding fragment thereof of claim 7, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 26, and wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 30.

### Claim 9 (depends on 7)

The antibody or antigen binding fragment thereof of claim 7, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 27, and wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 31.

### Claim 10 (depends on 7)

The antibody or antigen binding fragment thereof of claim 7, wherein the heavy chain variable region comprises is the amino acid sequence of SEQ ID NO: 28, and wherein the light chain variable region comprises is the amino acid sequence of SEQ ID NO: 32.

### Claim 11 (depends on 9)

The antibody or antigen binding fragment thereof of claim 9, wherein the antibody comprises two heavy chains and two light chains.

### Claim 12 (depends on 3)

The antibody or antigen binding fragment thereof of claim 3, wherein the antibody comprises a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:17, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 18, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:19, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:20, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:22.

### Claim 13 (depends on 1)

A composition comprising the antibody or antigen binding fragment thereof of claim 1 and a pharmaceutically acceptable carrier or diluent.

### Claim 14 (depends on 13)

The composition of claim 13, further comprising an agent selected from the group consisting of:
a. an anti-PD1 antibody or an antigen binding fragment thereof;
b. an anti-LAG3 antibody or an antigen binding fragment thereof;
c. an anti-VISTA antibody or an antigen binding fragment thereof;
d. an anti-BTLA antibody or an antigen binding fragment thereof;
e. an anti-TIM3 antibody or an antigen binding fragment thereof;
f. an anti-CTLA4 antibody or an antigen binding fragment thereof;
g. an anti-HVEM antibody or an antigen binding fragment thereof;
h. an anti-CD27 antibody or an antigen binding fragment thereof;
i. an anti-CD137 antibody or an antigen binding fragment thereof;
j. an anti-OX40 antibody or an antigen binding fragment thereof;
k. an anti-CD28 antibody or an antigen binding fragment thereof;
l. an anti-PDL1 antibody or an antigen binding fragment thereof;
m. an anti-PDL2 antibody or an antigen binding fragment thereof;
n. an anti-GITR antibody or an antigen binding fragment thereof;
o. an anti-ICOS antibody or an antigen binding fragment thereof;
p. an anti-SIRPα antibody or an antigen binding fragment thereof;
q. an anti-ILT2 antibody or an antigen binding fragment thereof;
r. an anti-ILT3 antibody or an antigen binding fragment thereof;
s. an anti-ILT4 antibody or an antigen binding fragment thereof; and
t. an anti-ILT5 antibody or an antigen binding fragment thereof.

### Claim 15 (depends on 14)

The composition of claim 14, wherein the anti-PD1 antibody or an antigen binding fragment thereof is selected from the group consisting of: pembrolizumab or an antigen binding fragment thereof and nivolumab or an antigen binding fragment thereof.

### Claim 16 (depends on 15)

The composition of claim 15, wherein the anti-PD1 antibody is pembrolizumab.

### Claim 17

An antibody or antigen binding fragment thereof that binds to human T cell immunoreceptor with Ig and ITIM domains (TIGIT) comprising a light chain immunoglobulin, a heavy chain immunoglobulin or both a light chain and a heavy chain immunoglobulin, selected from the group consisting of:
a. an antibody or antigen binding fragment thereof comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8;
b. an antibody or antigen binding fragment thereof comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:9 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:13;
c. an antibody or antigen binding fragment thereof comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 23 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:24;
d. an antibody or antigen binding fragment thereof comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 25 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:29;
e. an antibody or antigen binding fragment thereof comprising a heavy chain variable region selected from the group consisting of SEQ ID NOs: 10, 11, 12, 48, 49, 50, 51, 52, 53, 54, 55, and 56 and a light chain variable region selected from the group consisting of SEQ ID NOs: 14, 15, 16, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, and 80;
f. an antibody or antigen binding fragment thereof comprising a heavy chain variable region selected from the group consisting of SEQ ID NOs: 26, 27, 28, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, and 112 and a light chain variable region selected from the group consisting of SEQ ID NOs: 30, 31, and 32;
g. an antibody or antigen binding fragment thereof comprising a heavy chain variable region comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs: 10, 11, 12, 48, 49, 50, 51, 52, 53, 54, 55, or 56 and a light chain variable region comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs: 14, 15, 16, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80;
h. an antibody or antigen binding fragment thereof comprising a heavy chain variable region comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs: 26, 27, 28, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, or 112 and a light chain variable region comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs: 30, 31, or 32;
i. an antibody or antigen binding fragment thereof comprising a heavy chain variable region comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs: 10, 11, 12, 48, 49, 50, 51, 52, 53, 54, 55, or 56 and a light chain variable region comprising at least 90%, 95%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs: 14, 15, 16, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80, wherein any sequence variations occur in the framework regions of the antibody; and
j. an antibody or antigen binding fragment thereof comprising a heavy chain variable region comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs: 26, 27, 28, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, or 112 and a light chain variable region comprising at least 90%, 95%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs: 30, 32, or 32, wherein any sequence variations occur in the framework regions of the antibody.

### Claim 18

A humanized antibody that binds to human T cell immunoreceptor with Ig and ITIM domains (TIGIT), wherein the antibody wherein the humanized antibody comprises two heavy chains and two light chains, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 27, and wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 31.

### Claim 19

A humanized antibody that binds to human T cell immunoreceptor with Ig and ITIM domains (TIGIT), wherein the humanized antibody comprises a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:17, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 18, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:19, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:20, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:22, wherein the humanized antibody comprises two heavy chains and two light chains.

### Claim 20

A humanized antibody that binds to human T cell immunoreceptor with Ig and ITIM domains (TIGIT), wherein the antibody comprises two heavy chains and two light chains, wherein each heavy chain comprises a heavy chain variable region and each light chain comprises a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence the amino acid sequence of SEQ ID NO: 27, wherein the light chain variable region comprises the amino acid sequence the amino acid sequence of SEQ ID NO: 31, wherein the antibody comprises a human IgG1 constant domain comprising the amino acid sequence of SEQ ID NO: 44 and a human kappa constant domain comprising the amino acid sequence of SEQ ID NO: 43.

### Claim 21

A humanized antibody that binds to human T cell immunoreceptor with Ig and ITIM domains (TIGIT), wherein the antibody comprises two heavy chains and two light chains, wherein each heavy chain comprises a heavy chain variable region and each light chain comprises a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence the amino acid sequence of SEQ ID NO: 27, wherein the light chain variable region comprises the amino acid sequence the amino acid sequence of SEQ ID NO: 31, wherein the antibody comprises a human IgG4 constant domain comprising the amino acid sequence of SEQ ID NO: 42 and a human kappa constant domain comprising the amino acid sequence of SEQ ID NO: 43.

### Claim 22 (depends on 1)

A method for detecting the presence of a T cell immunoreceptor with Ig and ITIM domains (TIGIT) peptide or a fragment thereof in a sample comprising contacting the sample with the antibody or the antigen binding fragment thereof of claim 1 and detecting the presence of a complex between the antibody or the antigen binding fragment thereof and the peptide or the fragment thereof; wherein detection of the complex indicates the presence of the TIGIT peptide or a fragment thereof.