# US 2024/0189352 A1 · T-cell receptors specific for both rac1- and rac2-derived mutated epitopes

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- Number: US 2024/0189352 A1
- Document ID: US20240189352A1
- Status: Published application
- Kind: A1
- Application number: 18/286,933
- Filed: 2022-04-14
- Published: 2024-06-13
- Earliest claimed: 2021-04-15
- Assignees: Max-DelbrüCk-Centrum FüR Molekulare Medizin In Der Helmholtz-Gemeinschaft; Charite-Universitatsmedizin Berlin
- Applicants: MAX-DELBRÜCK-CENTRUM FÜR MOLEKULARE MEDIZIN in der Helmholtz-Gemeinschaft; Charité - Universitätsmedizin Berlin
- Inventors: Thomas BLANKENSTEIN; Gerald WILLIMSKY
- Web page: https://patentgrep.com/patent/US20240189352A1

## CPC

- 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)
- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- C12N 15/86: Viral vectors
- C12N 2740/10041: Use of virus, viral particle or viral elements as a vector
- 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)
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The invention is based on antigen binding proteins (ABPs) such as T-cell receptors (TCR) expressed on T-cells, which have a specificity to bind to MIC presented Rac2 and Rac1 derived neo-epitopes. Hence, such MHC presented peptides are derived from mutated versions of Rac1 and Rac2, such as preferably RAC2P29L and/or RAC1P29S. Provided are isolated ABPs as well as genetic constructs expressing the ABPs, recombinant host cells harboring the ABP of the invention and methods for producing such ABPs and host cells. Moreover, provided are medical applications involving the TCR of the invention, for example in context of an adoptive T-cell therapy.

## Claims

### Claim 1

An isolated antigen binding protein (ABP) which specifically binds to a mutated RAC1 and/or RAC2 derived antigenic peptide, or to a variant thereof, and wherein the isolated ABP comprises a T cell receptor (TCR) α or γ chain; and/or a TCR β or δ chain; wherein the TCR α or γ chain comprises a complementary determining region (CDR)3 having an amino acid sequence with at least 80% sequence identity to, or having no more than three amino acid substitution(s), deletion(s) or insertion(s) compared to, a sequence selected from SEQ ID Nos: 3 and 11; and/or wherein the TCR β or δ chain comprises a CDR3 having an amino acid sequence with at least 80% sequence identity to, or having no more than three amino acid substitution(s), deletion(s) or insertion(s) compared to, a sequence selected from SEQ ID Nos: 7 and 15.

### Claim 2 (depends on 1)

The isolated ABP of claim 1, wherein said ABP is capable of specifically and/or selectively binding to an antigenic peptide comprising the P29 mutated amino acid position of RAC1 and/or RAC2, preferably the antigenic peptide of SEQ ID NO: 17 and/or 18.

### Claim 3 (depends on 1, 2)

The isolated ABP of claim 1 or 2, wherein the ABP is a TCR, or an antigen binding derivative or fragment thereof.

### Claim 4 (depends on 1, 2, 3)

The isolated ABP of any one of claims 1 to 3, wherein the TCR α or γ chain further comprises a CDR1 having an amino acid sequence with at least 80% sequence identity to, or having no more than three amino acid substitution(s), deletion(s) or insertion(s) compared to, a sequence selected from SEQ ID Nos: 1 or 9; and/or a CDR2 having an amino acid sequence with at least 80% sequence identity to, or having no more than three amino acid substitution(s), deletion(s) or insertion(s) compared to, a sequence selected from SEQ ID Nos: 2, or 10.

### Claim 5 (depends on 1, 2, 3, 4)

The isolated ABP of any one of claims 1 to 4, wherein the TCR β or δ chain further comprises a CDR1 having an amino acid sequence with at least 80% sequence identity to, or having no more than three amino acid substitution(s), deletion(s) or insertion(s) compared to, a sequence selected from SEQ ID Nos: 5, and 13; and/or a CDR2 having an amino acid sequence with at least 80% sequence identity to, or having no more than three amino acid substitution(s), deletion(s) or insertion(s) compared to, a sequence selected from SEQ ID Nos: 6 and 14.

### Claim 6 (depends on 1, 2, 3, 4, 5)

The isolated ABP of any one of claims 1 to 5, comprising a TCR variable chain region having at least 80% sequence identity to, or having no more than 20 amino acid substitution(s), deletion(s) or insertion(s) compared to, an amino acid sequence selected from SEQ ID Nos. 4, 8, 12, and 16.

### Claim 7 (depends on 1, 2, 3, 4, 5, 6)

The isolated ABP of any one of claims 1 to 6, wherein the ABP is a TCR, or an antigen-binding fragment or derivative thereof, further comprising a TCR constant region, preferably a human TCR constant region sequence.

### Claim 8 (depends on 1, 2, 3, 4, 5, 6, 7)

An isolated nucleic acid encoding for an ABP of any one of claims 1 to 7.

### Claim 9 (depends on 8)

A recombinant vector comprising a nucleic acid of claim 8.

### Claim 10 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9)

A recombinant host cell comprising an ABP of any one of claims 1 to 7, or a nucleic acid of claim 8, or a vector of claim 9.

### Claim 11 (depends on 10)

The recombinant host cell of claim 10, wherein the cell is a lymphocyte, preferably a T lymphocyte or T lymphocyte progenitor, more preferably a CD4 or, most preferably, a CD8 positive T-cell.

### Claim 12 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11)

A pharmaceutical composition comprising the ABP of any one of claims 1 to 7, or a nucleic acid of claim 8, or a vector of claim 9, or the host cell of claim 10 or 11, and a pharmaceutical acceptable carrier, stabilizer and/or excipient; preferably, wherein the pharmaceutical composition comprises at least two different ABP of any one of claims 1 to 7.

### Claim 13 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12)

A compound or composition for use in medicine, wherein the compound or composition is selected from the ABP of any one of claims 1 to 7, or a nucleic acid of claim 8, or a vector of claim 9, or the recombinant host cell of claim 10 or 11, or the pharmaceutical composition of claim 12.

### Claim 14 (depends on 13)

The compound or composition for use of claim 13, wherein the treatment comprises immune therapy, preferably adoptive, autologous or heterologous T-cell therapy, involving the use of said cell comprising the ABP or nucleic acid of any one of the preceding claims.

### Claim 15 (depends on 1, 2, 3, 4, 5, 6, 7)

A method of manufacturing a RAC2P29L and/or RAC1P29S specific antigen recognizing construct expressing cell line, comprising
(a) providing a suitable host cell,
(b) providing a genetic construct comprising a coding sequence encoding the ABP according to any of claims 1 to 7,
(c) introducing into said suitable host cell said genetic construct,
(d) expressing said genetic construct by said suitable host cell to obtain the specific antigen recognizing construct expressing cell line.