# US 12,698,316 B2 · Engineered immune-mobilizing T-cell receptors with enhanced affinity for HIV-1 gag

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- Number: US 12,698,316 B2
- Document ID: US12698316B2
- Status: Granted
- Kind: B2
- Application number: 17/817,301
- Filed: 2022-08-03
- Published: 2023-06-22
- Granted: 2026-08-04
- Earliest claimed: 2016-06-23
- Assignees: Immunocore Limited
- Applicants: Immunocore Limited
- Inventors: Tara Mahon; Yi Li
- Web page: https://patentgrep.com/patent/US12698316B2

## CPC

- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- A61P 31/18: for HIV
- C07K 16/2809: {against the T-cell receptor (TcR)-CD3 complex}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61K 47/6425: {the peptide or protein in the drug conjugate being a receptor, e.g. CD4, a cell surface antigen, i.e. not a peptide ligand targeting the antigen, or a cell surface determinant, i.e. a part of the surface of a cell}
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- 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 relates to T cell receptors (TCRs) which bind the HLA-A*02 restricted peptide SLYNTVATL (SEQ ID NO: 1) derived from the HIV Gag gene product, p17. Said TCRs comprise non-natural mutations within the alpha and/or beta variable domains relative to a native HIV TCR. The TCRs of the invention possess unexpectedly high affinity, specificity and sensitivity for a complex of SEQ ID NO: 1 and HLA-A*02, and drive a particularly potent T cell response. Such TCRs are particularly useful in the development of soluble immunotherapeutic reagents for the treatment of HIV infected individuals.

## Claims

### Claim 1

A soluble T cell receptor (TCR)-anti-CD3 fusion molecule that specifically binds to SLYNTVATL (SEQ ID NO: 1) in complex with HLA-A*02 comprising a TCR alpha chain comprising a TCR alpha chain variable domain and a TCR beta chain comprising a TCR beta chain variable domain, wherein
(i) the TCR alpha chain variable domain comprises an amino acid sequence comprising at least 94% sequence identity to SEQ ID NO: 6; and
(ii) the TCR beta chain variable domain comprises an amino acid sequence comprising the sequence of SEQ ID NO: 8;
wherein an anti-CD3 antibody is covalently linked to the N-terminus or the C-terminus of the TCR beta chain.

### Claim 2 (depends on 1)

The soluble TCR-anti-CD3 fusion molecule of claim 1, wherein the TCR alpha chain variable domain comprises a CDR1 sequence of SEQ ID NO: 26 and a CDR2 sequence of SEQ ID NO: 27.

### Claim 3 (depends on 2)

The soluble TCR-anti-CD3 fusion molecule of claim 2, wherein the TCR beta chain variable domain comprises a CDR1 sequence of SEQ ID NO: 23, a CDR2 sequence of SEQ ID NO: 28, and a CDR3 sequence of SEQ ID NO: 25.

### Claim 4 (depends on 1)

The soluble TCR-anti-CD3 fusion molecule of claim 1, which is an alpha-beta heterodimer, having a TCR alpha chain TRAC constant domain sequence and a TCR beta chain TRBC1 or TRBC2 constant domain sequence, optionally wherein the TCR alpha and beta chain constant domain sequences are modified by truncation or substitution to delete the native disulfide bond between Cys4 of exon 2 of TRAC and Cys2 of exon 2 of TRBC 1 or TRBC2, wherein the TCR alpha and beta chain constant domain sequence(s) are modified by substitution of cysteine residues for Thr 48 of TRAC and Ser 57 of TRBC1 or TRBC2, the said cysteines forming a disulfide bond between the TCR alpha and beta constant domains of the soluble TCR-anti-CD3 fusion molecule.

### Claim 5 (depends on 1)

The soluble TCR-anti-CD3 fusion molecule of claim 1, comprising a TCR in single chain format of the type Va-L-Vb, Vb-L-Va, Va-Ca-L-Vb, Va-L-Vb-Cb, Va-Ca-L-Vb-Cb, or Vb-Cb-L-Va-Ca, wherein Va and Vb are TCR alpha and beta variable regions respectively, Ca and Cb are TCR alpha and beta constant regions respectively, and L is a linker sequence.

### Claim 6 (depends on 1)

The soluble TCR-anti-CD3 fusion molecule of claim 1, wherein the anti-CD3 antibody is covalently linked via a linker sequence selected from the group consisting of GGGGS (SEQ ID NO: 12), GGGSG (SEQ ID NO: 13), GGSGG (SEQ ID NO: 14), GSGGG (SEQ ID NO: 15), GSGGGP (SEQ ID NO: 16), GGEPS (SEQ ID NO: 17), GGEGGGP (SEQ ID NO: 18), and GGEGGGSEGGGS (SEQ ID NO: 19).