# US 12,760,110 B2 · Binders and chimeric antigen receptors which specifically bind fibroblast growth factor receptor 4

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- Number: US 12,760,110 B2
- Document ID: US12760110B2
- Status: Granted
- Kind: B2
- Application number: 18/027,305
- Filed: 2021-10-08
- Published: 2024-01-25
- Granted: 2026-10-13
- Earliest claimed: 2020-10-09
- Assignees: Seattle Children's Hospital
- Applicants: Seattle Children's Hospital; University of Pittsburgh—Of the Commonwealth System of Higher Education
- Inventors: Rimas J. Orentas; Dimiter Stanchev Dimitrov; Wei Li; Du-Sun Baek
- Web page: https://patentgrep.com/patent/US12760110B2

## CPC

- C07K 16/2863: {against receptors for growth factors, growth regulators}
- A61K 35/17: Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes (when activated by a specific antigen A61K39/00)
- A61K 40/31: Chimeric antigen receptors [CAR]
- C12N 5/0634: {Cells from the blood or the immune system}
- C12N 15/86: Viral vectors
- A61K 2239/21: Transmembrane domain
- A61K 2239/22: Intracellular domain
- C12N 2510/00: Genetically modified cells
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Some embodiments of the methods and compositions provided herein include methods and materials involved in binding a binder (e.g., an antibody, antigen binding fragment, antibody domain, CAR, cell engager, and/or ADC) to an FGFR4 polypeptide. For example, binders (e.g., antibodies, antigen binding fragments, antibody domains, CARs, cell engagers, and/or ADCs) acidic box that bind to an FGFR4 polypeptide and methods and materials for using one or more such binding molecules to treat a mammal (e.g., a human) having cancer are provided. Some embodiments of the methods and compositions provided herein include chimeric antigen receptors (CARs) which specifically bind to fibroblast growth factor receptor 4 (FGFR4). Some embodiments include nucleic acids encoding such CARs, and cells containing such CARs. Some embodiments include the use of such CARs in safe and effective therapies for a cancer, such as an FGFR4-expressing cancer, such as a rhabdomyosarcoma.

## Claims

### Claim 1

A chimeric antigen receptor (CAR) comprising:
(a) an antigen binding region which specifically binds an IgIII membrane-proximal domain of a human fibroblast growth factor receptor 4 (FGFR4) protein, comprising:
(i) a complementarity determining region 1 of a heavy chain variable region (H-CDR1) comprising the amino acid sequence set forth in SEQ ID NO:132,
(ii) an H-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 133,
(iii) an H-CDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 74, 98, 110, 134 and 146,
(iv) a complementarity determining region 1 of a light chain variable region (L-CDR1) comprising the amino acid sequence set forth in SEQ ID NO:135,
(v) an L-CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 136,
(vi) an L-CDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 77, 101 and 137;
(b) a transmembrane domain; and
(c) an intracellular signaling domain.

### Claim 2 (depends on 1)

The CAR of claim 1, wherein the L-CDR3 comprises the amino acid sequence of SEQ ID NO: 137.

### Claim 3 (depends on 2)

The CAR of claim 2, wherein the H-CD3 comprises the amino acid sequence of SEQ ID NO:134.

### Claim 4 (depends on 1)

The CAR of claim 1, wherein:
(i) the light chain variable region comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 174, 194 and 224; and
(ii) the heavy chain variable region comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 176, 196, 206, 226 and 236.

### Claim 5 (depends on 4)

The CAR of claim 4, wherein the light chain variable region comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:224.

### Claim 6 (depends on 5)

The CAR of claim 5, wherein the heavy chain variable region comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:226.

### Claim 7 (depends on 4)

The CAR of claim 4, wherein the antigen binding region comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 09-22.

### Claim 8 (depends on 7)

The CAR of claim 7, wherein the antigen binding region comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:19 or SEQ ID: 20.

### Claim 9 (depends on 1)

The CAR of claim 1, further comprising a polypeptide spacer located between the antigen binding domain and the transmembrane domain.

### Claim 10 (depends on 9)

The CAR of claim 9, wherein the polypeptide spacer comprises a hinge domain.

### Claim 11 (depends on 10)

The CAR of claim 10, wherein the polypeptide spacer comprises a CD28 hinge domain.

### Claim 12 (depends on 1)

The CAR of claim 1, wherein the transmembrane domain comprises a CD8 transmembrane domain or a CD28 transmembrane domain.

### Claim 13 (depends on 12)

The CAR of claim 12, wherein the transmembrane domain comprises the CD28 transmembrane domain.

### Claim 14 (depends on 1)

The CAR of claim 1, wherein the intracellular signaling domain comprises a costimulatory domain selected from the group consisting of CD27, CD28, 4-1BB, OX-40, CD30, CD40, PD-1, ICOS, LFA-1, CD2, CD7, NKG2C, B7-H3, and CD3-zeta.

### Claim 15 (depends on 14)

The CAR of claim 14, wherein the intracellular signaling domain comprises the 4-1BB domain and the CD3-zeta domain.

### Claim 16 (depends on 1)

A nucleic acid encoding the CAR of claim 1.

### Claim 17 (depends on 1)

A cell comprising the CAR of claim 1.

### Claim 18 (depends on 17)

The cell of claim 17, wherein the cell is a T cell, a stem cell, a precursor T-cell, or a hematopoietic stem cell or an NK cell.

### Claim 19 (depends on 17)

A pharmaceutical composition comprising the cell of claim 17 and a pharmaceutically acceptable excipient.

### Claim 20 (depends on 17)

A method of treating, inhibiting or ameliorating a cancer in a subject, comprising: administering the cell of claim 17 to the subject, wherein the cancer comprises an FGFR4-expressing cell.