# US 11,433,100 B2 · Compositions and methods for treating ceacam positive cancers

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- Number: US 11,433,100 B2
- Document ID: US11433100B2
- Status: Granted
- Kind: B2
- Application number: 17/517,559
- Filed: 2021-11-02
- Published: 2022-02-24
- Granted: 2022-09-06
- Earliest claimed: 2020-08-20
- Assignees: A2 Biotherapeutics, Inc.
- Applicants: A2 Biotherapeutics, Inc.
- Inventors: Xueyin Wang; Carl Alexander Kamb; Han Xu; Mark L. Sandberg; Dora Toledo Warshaviak
- Web page: https://patentgrep.com/patent/US11433100B2

## CPC

- C07K 14/70578: {NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 (NGF-receptor C07K14/71, TNF-receptor C07K14/7151)}
- A61K 39/001111: {Immunoglobulin superfamily}
- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- A61K 40/31: Chimeric antigen receptors [CAR]
- A61K 40/32: T-cell receptors [TCR]
- A61K 40/4266: {Carcinoembryonic antigen [CEA]}
- A61P 35/00: Antineoplastic agents
- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- C07K 14/70517: {CD8}
- C07K 14/70521: {CD28, CD152}
- C07K 14/70539: {MHC-molecules, e.g. HLA-molecules}
- C07K 16/2833: {against MHC-molecules, e.g. HLA-molecules}
- C07K 16/3007: {Carcino-embryonic Antigens}
- A61K 2239/50: Colon
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2319/00: Fusion polypeptide
- C07K 2319/03: containing a transmembrane segment
- C07K 2319/33: fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
- 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

## Abstract

The disclosure provides immune cells comprising a first activator receptor specific to CEA, and a second inhibitory receptor, and methods of making and using same for the treatment of cancer.

## Claims

### Claim 1

An immune cell comprising:
a. a first receptor, comprising an extracellular ligand binding domain specific to CEA cell adhesion molecule 5 (CEA); and
b. a second receptor, comprising an extracellular ligand binding domain specific to HLA-A*02,
wherein the first receptor is an activator receptor responsive to CEA; and wherein the second receptor is an inhibitory receptor responsive to HLA-A*02;
wherein the extracellular ligand binding domain of the first receptor comprises a variable heavy (VH) portion comprising complementarity determining regions (CDRs) CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NOs: 55, 56, and 57, respectively, and a variable light (VL) portion comprising CDRs CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NOs: 59, 61, and 63, respectively; and
wherein the extracellular ligand binding domain of the second receptor comprises a VH portion comprising CDRs CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NOs: 106, 107, and 108, respectively, and a VL portion comprising CDRs CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NOs: 103, 104, and 105, respectively.

### Claim 2 (depends on 1)

The immune cell of claim 1, wherein the extracellular ligand binding domain of the first receptor comprises a VH portion comprising SEQ ID NO: 144 or a sequence having at least 85% identity thereto, and a VL portion comprising SEQ ID NO: 148 or a sequence having at least 85% identity thereto.

### Claim 3 (depends on 1)

The immune cell of claim 1, wherein the extracellular ligand binding domain of the second receptor comprises a VH portion comprising SEQ ID NO: 981 or a sequence having at least 85% identity thereto, and a VL portion comprising SEQ ID NO: 166 or a sequence having at least 85% identity thereto.

### Claim 4 (depends on 1)

The immune cell of claim 1, wherein the extracellular ligand binding domain of the first receptor comprises an scFv sequence of SEQ ID NO: 68 or a sequence having at least 85% identity thereto.

### Claim 5 (depends on 1)

The immune cell of claim 1, wherein the extracellular ligand binding domain of the second receptor comprises an scFv sequence of SEQ ID NO: 91 or a sequence having at least 85% identity thereto.

### Claim 6 (depends on 1)

The immune cell of claim 1, wherein the first receptor is a chimeric antigen receptor (CAR) comprising a hinge domain, a transmembrane domain and an intracellular domain.

### Claim 7 (depends on 6)

The immune cell of claim 6, wherein the hinge domain of the first receptor comprises a CD8α hinge domain.

### Claim 8 (depends on 7)

The immune cell of claim 7, wherein the CD8α hinge domain of the first receptor comprises a sequence of SEQ ID NO: 71, or a sequence having at least 85% identity thereto.

### Claim 9 (depends on 6)

The immune cell of claim 6, wherein the transmembrane domain of the first receptor comprises a CD28 transmembrane domain.

### Claim 10 (depends on 9)

The immune cell of claim 9, wherein the CD28 transmembrane domain of the first receptor comprises a sequence of SEQ ID NO: 75, or a sequence having at least 85% identity thereto.

### Claim 11 (depends on 6)

The immune cell of claim 6, wherein the intracellular domain of the first receptor comprises a CD28 co-stimulatory domain, a 4-1BB co-stimulatory domain, and a CD3ζ activation domain.

### Claim 12 (depends on 11)

The immune cell of claim 11, wherein the intracellular domain of the first receptor comprises a sequence of SEQ ID NO: 158, or a sequence having at least 85% identity thereto.

### Claim 13 (depends on 1)

The immune cell of claim 1, wherein the first receptor comprises a sequence of SEQ ID NO: 52, or a sequence having at least 90% identity thereto.

### Claim 14 (depends on 1)

The immune cell of claim 1, wherein the second receptor comprises a LILRB1 intracellular domain.

### Claim 15 (depends on 14)

The immune cell of claim 14, wherein the LILRB1 intracellular domain comprises a sequence at least 90%, or is identical to SEQ ID NO: 131.

### Claim 16 (depends on 1)

The immune cell of claim 1, wherein the second receptor comprises a LILRB1 transmembrane domain.

### Claim 17 (depends on 16)

The immune cell of claim 16, wherein the LILRB1 transmembrane domain comprises a sequence at least 90% or is identical to SEQ ID NO: 135.

### Claim 18 (depends on 1)

The immune cell of claim 1, wherein the second receptor comprises a LILRB1 hinge domain.

### Claim 19 (depends on 18)

The immune cell of claim 18, wherein the LILRB1 hinge domain comprises a sequence at least 90% or is identical to SEQ ID NO: 134.

### Claim 20 (depends on 1)

The immune cell of claim 1, wherein the second receptor comprises a sequence of SEQ ID NO: 164, or a sequence having at least 90% identity thereto.

### Claim 21 (depends on 1)

The immune cell of claim 1, wherein the immune cell is a T cell, an NK cell or a macrophage.

### Claim 22 (depends on 1)

A pharmaceutical composition, comprising a therapeutically effective amount of the immune cell of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

### Claim 23 (depends on 1)

The immune cell of claim 1, wherein the extracellular ligand binding domain of the second receptor comprises a VH portion comprising SEQ ID NO: 981 or a sequence having at least at least 95% thereto, and a VL portion comprising SEQ ID NO: 166 or a sequence having at least 95% identity thereto.

### Claim 24 (depends on 23)

The immune cell of claim 23, wherein the extracellular ligand binding domain of the first receptor comprises a VH portion comprising SEQ ID NO: 144 or a sequence having at least 95% thereto, and a VL portion comprising SEQ ID NO: 148 or a sequence at least 95% identity thereto.

### Claim 25 (depends on 23)

The immune cell of claim 23, wherein the extracellular ligand binding domain of the first receptor comprises an scFv sequence of SEQ ID NO: 68 or at least 95% identity thereto.

### Claim 26 (depends on 1)

The immune cell of claim 1, wherein the extracellular ligand binding domain of the second receptor comprises an scFv sequence of SEQ ID NO: 91 or a sequence having at least 95% identity thereto.

### Claim 27 (depends on 1)

The immune cell of claim 1, wherein the extracellular ligand binding domain of the second receptor comprises a VH portion comprising SEQ ID NO: 981, and a VL portion comprising SEQ ID NO: 166.

### Claim 28 (depends on 27)

The immune cell of claim 27, wherein the extracellular ligand binding domain of the first receptor comprises a VH portion comprising SEQ ID NO: 144, and a VL portion comprising SEQ ID NO: 148.

### Claim 29 (depends on 1)

The immune cell of claim 1, wherein the extracellular ligand binding domain of the first receptor comprises an scFv sequence of SEQ ID NO: 68; and wherein the extracellular ligand binding domain of the second receptor comprises an scFv sequence of SEQ ID NO: 91.

### Claim 30 (depends on 1)

The immune cell of claim 1, wherein the immune cell is a T cell.