# US 12,686,722 B2 · Anti-HVEM antibodies and use thereof

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- Number: US 12,686,722 B2
- Document ID: US12686722B2
- Status: Granted
- Kind: B2
- Application number: 17/607,189
- Filed: 2020-04-28
- Published: 2022-07-21
- Granted: 2026-07-21
- Earliest claimed: 2019-04-29
- Assignees: 4C Biomed Limited; Tel HaShomer Medical Research Infrastructure and Services Ltd.
- Applicants: 4C Biomed Limited; Tel Hashomer Medical Research Infrastructure and Services Ltd.
- Inventors: Eyal Greenberg; Gilli Galore-Haskel; Efrat Merhavi-Shoham; Gal Markel; Jacob Schachter
- Web page: https://patentgrep.com/patent/US12686722B2

## CPC

- C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95}
- G01N 33/6872: {Intracellular protein regulatory factors and their receptors, e.g. including ion channels}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 35/00: Antineoplastic agents
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/30: from tumour cells
- C07K 16/3053: {Skin, nerves, brain}
- G01N 33/5759: {involving compounds localised on the membrane of tumour or cancer cells}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/74: Inducing cell proliferation
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- G01N 2333/70578: NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30 CD40 or CD95
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- 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)
- 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

## Abstract

Agents that bind HVEM, inhibit HVEM-BTLA interaction and activate downstream HVEM signaling are provided. Methods of treating disease with those agents and kits comprising those agents are also provided.

## Claims

### Claim 1

An antibody or antigen binding fragment thereof comprises three heavy chain CDRs (CDR-H) and three light chain CDRs (CDR-L), wherein: CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1 (SYAMS), CDR-H2 comprises the amino acid sequence as set forth in SEQ ID NO: 2 (AISGSGGSTYYADSVKG), CDR-H3 comprises the amino acid sequence as set forth in SEQ ID NO: 3 (APGDYTAYFDY), CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4 (RASQSVSSYLA), CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5 (GASSRAT), and CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 6 (QQYGSSPPYT).

### Claim 2 (depends on 1)

The antibody or antigen binding fragment thereof of claim 1, comprising a heavy chain comprising the sequence
(SEQ ID NO: 7)
QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSA
ISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKAP
GDYTAYFDYWGQGTLVTVSS.

### Claim 3 (depends on 1)

The antibody or antigen binding fragment thereof of claim 1, comprising a light chain comprising the sequence
(SEQ ID NO: 8)
ELVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYG
ASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPPYTFG
QGTKVEIK.

### Claim 4 (depends on 1)

The antibody or antigen binding fragment thereof of claim 1, comprising a heavy chain comprising the sequence MGWSCIILFLVATATGVHSQVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYA MSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMN SLRAEDTAVYYCAKAPGDYTAYFDYWGQGTLVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV VTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPR EEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR EPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 9) and a light chain comprising the sequence
(SEQ ID NO: 10)
MGWSCIILFLVATATGVHSELVLTQSPATLSLSPGERATLSCRASQSVSS
YLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPE
DFAVYYCQQYGSSPPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTA
SVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC.

### Claim 5 (depends on 1)

A pharmaceutical composition comprising an antibody or antigen binding fragment thereof of claim 1 and a pharmaceutically acceptable carrier, excipient or adjuvant.

### Claim 6 (depends on 5)

A method of treating a disease or condition characterized by HVEM positive cells in a subject in need thereof, the method comprising administering the pharmaceutical composition of claim 5, thereby treating said disease or condition.

### Claim 7 (depends on 6)

The method of claim 6, further comprising administering an anti-PD-1/PD-L1 based immunotherapy.

### Claim 8 (depends on 6)

The method of claim 6, further comprising administering adoptive cell therapy, adoptive tumor infiltrating lymphocyte (TIL) therapy, or a chimeric antigen receptor (CAR) expressing immune cell, wherein said CAR targets a non-HVEM protein on a surface of said HVEM expressing cells.

### Claim 9 (depends on 6)

The method of claim 6, wherein said disease or condition is an HVEM positive cancer or precancerous lesion.

### Claim 10 (depends on 9)

The method of claim 9, wherein said HVEM positive cancer is selected from skin cancer, lung cancer and colon cancer.

### Claim 11 (depends on 6)

The method of claim 6, wherein said disease or condition is an infectious disease and wherein said infected cells comprise HVEM expression.

### Claim 12 (depends on 6)

A method of determining suitability of a subject to be treated by a method of claim 6, comprising obtaining a disease sample from said subject and determining HVEM levels in said sample, wherein elevated expression of HVEM as compared to a healthy sample or predetermined threshold indicates the subject is suitable for a method of treatment of claim 6.

### Claim 13 (depends on 1)

A method of detecting HVEM in a sample, the method comprising contacting said sample with an antibody or antigen binding fragment thereof of claim 1, thereby detecting HVEM.

### Claim 14 (depends on 5)

A kit comprising, the pharmaceutical composition of claim 5 and at least one of:
a. an anti-PD-1/PD-L1 based immunotherapy;
b. a label stating the pharmaceutical composition of the invention is for use with an anti-PD-1/PD-L1 based immunotherapy; and
c. a secondary detection molecule.