# US 11,897,957 B2 · Anti-ILT4 antibodies and antigen-binding fragments

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- Number: US 11,897,957 B2
- Document ID: US11897957B2
- Status: Granted
- Kind: B2
- Application number: 17/338,597
- Filed: 2021-06-03
- Published: 2022-02-03
- Granted: 2024-02-13
- Earliest claimed: 2017-04-07
- Assignees: Merck Sharp & Dohme Corp.; Agenus Inc.
- Applicants: Merck Sharp & Dohme LLC; Agenus Inc.
- Inventors: Milan Blanusa; Barbara Joyce-Shaikh; Andrea Claudia Schuster; Kornelia Schultze; Luis A. Zuniga
- Web page: https://patentgrep.com/patent/US11897957B2

## CPC

- C07K 16/2803: {against the immunoglobulin superfamily}
- A61P 35/00: Antineoplastic agents
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- 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: 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

The present invention provides antibodies and antigen-binding fragments thereof that bind to ILT4 (immunoglobulin-like transcript 4) and combinations thereof, e.g., with an anti-PD1 antibody. Also provided are methods of use thereof, for example, for treating or preventing cancer in a subject; and methods of making such antibodies and fragments.

## Claims

### Claim 1

A method of treating a cancer in a human subject in need thereof, comprising administering to the human subject an effective amount of an antibody or antigen-binding fragment thereof that binds human ILT4, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising: a CDR-H1 having an amino acid sequence of GYYWS (SEQ ID NO: 16), a CDR-H2 having an amino acid sequence of EINHSGSTNYNPSLKS (SEQ ID NO: 47) or EINHAGSTNYNPSLKS (SEQ ID NO: 48), and a CDR-H3 having an amino acid sequence of LPTRWVTTRYFDL (SEQ ID NO: 18); and a light chain variable domain comprising: a CDR-L1 having an amino acid sequence of TGSSSNIGAGYDVH (SEQ ID NO: 19), a CDR-L2 having an amino acid sequence of GNSNRPS(SEQ ID NO: 49), GQSNRPS(SEQ ID NO: 50), GESNRPS(SEQ ID NO: 51), GDSNRPS(SEQ ID NO: 52), GNANRPS(SEQ ID NO: 53), GQANRPS(SEQ ID NO: 54), GEANRPS(SEQ ID NO: 55), or GDANRPS(SEQ ID NO: 56), and a CDR-L3 having an amino acid sequence of QSFDNSLSAYV (SEQ ID NO: 21).

### Claim 2 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence set forth in SEQ ID NO:58, 70, 71, 72, 73, or 77, and a heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence set forth in SEQ ID NO:57, 63, or 69.

### Claim 3 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO:58, 70, 71, 72, 73, or 77, and a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO:57, 63, or 69.

### Claim 4 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment thereof comprises a light chain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence set forth in SEQ ID NO:3, 4, 5, 6, 7, or 45, and a heavy chain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence set forth in SEQ ID NO:1, 2, 79, 80, or 81.

### Claim 5 (depends on 1)

The method of claim 1, wherein the antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence set forth in SEQ ID NO:3, 4, 5, 6, 7, or 45, and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:1, 2, 79, 80, or 81.

### Claim 6

A method of treating a cancer in a human subject in need thereof, comprising administering to the human subject an effective amount of an antibody or antigen-binding fragment thereof that binds human ILT4, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising: a CDR-H1 having an amino acid sequence of GYYWS (SEQ ID NO: 16), a CDR-H2 having an amino acid sequence of EINHAGSTNYNPSLKS (SEQ ID NO: 48), and a CDR-H3 having an amino acid sequence of LPTRWVTTRYFDL (SEQ ID NO: 18); and a light chain variable domain comprising: a CDR-L1 having an amino acid sequence of TGSSSNIGAGYDVH (SEQ ID NO: 19), a CDR-L2 having an amino acid sequence of GDSNRPS (SEQ ID NO: 52), and a CDR-L3 having an amino acid sequence of QSFDNSLSAYV (SEQ ID NO: 21).

### Claim 7 (depends on 6)

The method of claim 6, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence set forth in SEQ ID NO:58, and a heavy chain variable domain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence set forth in SEQ ID NO:57.

### Claim 8 (depends on 6)

The method of claim 6, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO:58 and a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO:57.

### Claim 9 (depends on 6)

The method of claim 6, wherein the antibody or antigen-binding fragment thereof comprises a light chain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence set forth in SEQ ID NO:7 and a heavy chain comprising an amino acid sequence that is at least 90% identical to the amino acid sequence set forth in SEQ ID NO:2.

### Claim 10 (depends on 6)

The method of claim 6, wherein the antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence set forth in SEQ ID NO:7 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:2.

### Claim 11 (depends on 6)

The method of claim 6, wherein the antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence set forth in SEQ ID NO:7 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:80.

### Claim 12 (depends on 6)

The method of claim 6, further comprising administering a therapeutic agent to the human subject.

### Claim 13 (depends on 12)

The method of claim 12, wherein the therapeutic agent is an anti-PD-1 antibody.

### Claim 14 (depends on 13)

The method of claim 13, wherein the anti-PD-1 antibody is pembrolizumab.

### Claim 15 (depends on 13)

The method of claim 13, wherein the anti-PD-1 antibody is nivolumab.

### Claim 16 (depends on 6)

The method of claim 6, wherein the cancer is anaplastic astrocytoma, astrocytoma, bladder cancer, bone cancer, brain cancer, breast cancer, carcinoid cancer, cervical cancer, chondrosarcoma, choroid plexus papilloma, colorectal cancer, endometrial cancer, ependymoma, esophagus cancer, Ewing's sarcoma, gall bladder cancer, gastric cancer, glioblastoma, head and neck cancer, hepatoblastoma, hepatocellular carcinoma, idiopathic myelfibrosis, kidney cancer, leukemia, liver cancer, lung cancer, non-small cell lung cancer, lymphoma, medulloblastoma, melanoma, meningioma, Merkel cell cancer, mesothelioma, multiple myeloma, neuroblastoma, oligodendroglioma, osteosarcoma, ovarian cancer, pancreatic cancer, polycythemia vera, primitive neuroectodermal tumor, prostate cancer, renal cell cancer, renal transitional cell cancer, retinoblastoma, rhabdoid tumor of the kidney, rhabdomyosarcoma, salivary gland cancer, sarcoma, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, cutaneous squamous cell carcinoma, synovial sarcoma, thrombocythemia, thyroid cancer, uterine cancer, vestibular schwannoma, or Wilm's tumor.

### Claim 17

A method for blocking binding of ILT4 to HLA-G, HLA-A, HLA-B and/or HLA-F in a human subject in need thereof comprising administering to the human subject an effective amount of an antibody or antigen-binding fragment thereof that binds human ILT4, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising: a CDR-H1 having an amino acid sequence of GYYWS (SEQ ID NO: 16), a CDR-H2 having an amino acid sequence of EINHSGSTNYNPSLKS (SEQ ID NO: 47) or EINHAGSTNYNPSLKS (SEQ ID NO: 48), and a CDR-H3 having an amino acid sequence of LPTRWVTTRYFDL (SEQ ID NO: 18); and a light chain variable domain comprising: a CDR-L1 having an amino acid sequence of TGSSSNIGAGYDVH (SEQ ID NO: 19), a CDR-L2 having an amino acid sequence of GNSNRPS(SEQ ID NO: 49), GQSNRPS(SEQ ID NO: 50), GESNRPS(SEQ ID NO: 51), GDSNRPS(SEQ ID NO: 52), GNANRPS(SEQ ID NO: 53), GQANRPS(SEQ ID NO: 54), GEANRPS(SEQ ID NO: 55), or GDANRPS(SEQ ID NO: 56), and a CDR-L3 having an amino acid sequence of QSFDNSLSAYV (SEQ ID NO: 21).

### Claim 18

The method of 17, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising: a CDR-H1 having an amino acid sequence of GYYWS (SEQ ID NO: 16), a CDR-H2 having an amino acid sequence of EINHAGSTNYNPSLKS (SEQ ID NO: 48), and a CDR-H3 having an amino acid sequence of LPTRWVTTRYFDL (SEQ ID NO: 18); and a light chain variable domain comprising: a CDR-L1 having an amino acid sequence of TGSSSNIGAGYDVH (SEQ ID NO: 19), a CDR-L2 having an amino acid sequence of GDSNRPS (SEQ ID NO: 52), and a CDR-L3 having an amino acid sequence of QSFDNSLSAYV (SEQ ID NO: 21).

### Claim 19 (depends on 18)

The method of claim 18, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO:58 and a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO:57.

### Claim 20 (depends on 18)

The method of claim 18, wherein the antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence set forth in SEQ ID NO:7 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:2.

### Claim 21 (depends on 18)

The method of claim 18, wherein the antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence set forth in SEQ ID NO:7 and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:80.