TCRS specific for minor histocompatibility (H) antigen HA-1 and uses thereof

Patent metadata

Field	Value
Publication number	US-10538574-B2
Application number	US-201916362551-A
Country	US
Kind code	B2
Filing date	Mar 22, 2019
Priority date	Sep 23, 2016
Publication date	Jan 21, 2020
Grant date	Jan 21, 2020

Abstract

The present disclosure provides compositions and methods for targeting a minor histocompatibility (H) antigen (HA-1 H ) to, for example, prevent or manage relapse of a hematological malignancy after allogeneic hematopoietic stem cell transplantation (HCT). Also provided are transgene constructs encoding engineered binding proteins, such as a T cell receptor or a chimeric antigen receptor, optionally encoding additional components such as a co-receptor and/or safety switch. Such transgene constructs can be transduced into an immune cell, such as a T cell, and used as an immunotherapy in a subject having a hematological malignancy or at risk for recurrence of the hematological malignancy (e.g., leukemia, lymphoma, myeloma).

First claim

What is claimed is:

1. An engineered immune cell, comprising a heterologous polynucleotide encoding a binding protein that includes:
(a) a TCR α-chain variable (Vα) domain comprising a CDR3 amino acid sequence of SEQ ID NO: 88, a CDR2 amino acid sequence of SEQ ID NO: 136, and a CDR1 amino acid sequence of SEQ ID NO: 135, and;
(b) a TCR β-chain variable (Vβ) domain comprising a CDR3 amino acid sequence of SEQ ID NO: 14, a CDR2 amino acid sequence of SEQ ID NO: 134, and a CDR1 amino acid sequence of SEQ ID NO: 133,
wherein the encoded binding protein is capable of specifically binding to a peptide containing an HA-1H antigen and does not bind to a peptide that does not contain an HA-1H antigen.

2. The engineered immune cell of claim 1 , wherein the encoded binding protein is capable of specifically binding to a HA-1H peptide:HLA complex.

3. The engineered immune cell of claim 2 , wherein the HLA comprises HLA-A*0201.

4. The engineered immune cell of claim 1 , further comprising a heterologous polynucleotide encoding:
(a) a safety switch protein;
(b) a selection marker;
(c) a CD8 co-receptor β-chain; and/or
(d) a CD8 co-receptor α-chain.

5. The engineered immune cell of claim 1 , wherein
the encoded Vβ domain has at least 90% identity to the amino acid sequence of SEQ ID NO: 3 or 98, and the encoded Vα domain has at least 90% identity to the amino acid sequence of SEQ ID NO: 4 or 99.

6. The engineered immune cell of claim 5 , wherein
the encoded Vβ domain comprises the amino acid sequence of SEQ ID NO: 3 or 98, and the encoded Vα domain comprises the amino acid sequence of SEQ ID NO: 4 or 99.

7. The engineered immune cell of claim 1 , wherein the encoded binding protein comprises a TCR α-chain having at least 90% identity to the amino acid sequence of SEQ ID NO: 30 or 111.

8. The engineered immune cell of claim 1 , wherein the encoded binding protein comprises a TCR β-chain having at least 90% identity to the amino acid sequence of SEQ ID NO: 29 or 110.

9. The engineered immune cell of claim 1 , wherein the encoded binding protein comprises:
(i) a TCR β-chain comprising or consisting of the amino acid sequence of SEQ ID NO: 29, and a TCR α-chain comprising or consisting of the amino acid sequence of SEQ ID NO: 30; or
(ii) a TCR β-chain comprising or consisting of the amino acid sequence of SEQ ID NO: 110, and a TCR α-chain comprising or consisting of the amino acid sequence of SEQ ID NO: 111.

10. The engineered immune cell of claim 9 , wherein the (i) heterologous polynucleotide encoding the TCR α-chain and the (ii) heterologous polynucleotide encoding the TCR β-chain are contained in a single open reading frame, wherein the single open reading frame further comprises a polynucleotide encoding a self-cleaving peptide disposed between (i) and (ii).

11. The engineered immune cell of claim 10 , wherein the encoded binding protein comprises the amino acid sequence of SEQ ID NO: 54.

12. An engineered immune cell, comprising a heterologous transgene polynucleotide comprising or consisting of the nucleotide sequence of SEQ ID NO: 85.

13. The engineered immune cell of claim 1 , wherein the immune cell is a T cell, a NK cell, or a NK-T cell.

14. The engineered immune cell of claim 1 , wherein the peptide containing an HA-1H antigen comprises the amino acid sequence VLHDDLLEA (SEQ ID NO:66).

15. The engineered immune cell of claim 1 , wherein the Vα domain is encoded by a TRAV21 gene, and the Vβ domain is encoded by a TRBV7-9 gene.

16. The engineered immune cell of claim 15 , wherein the TRAV21 gene comprises TRAV21*02 and the TRBV7-9 gene comprises TRB7*03.

17. The engineered immune cell of claim 15 , wherein the heterologous polynucleotide encoding a binding protein further comprises a TRAJ40*01 gene, a TRBD1*01 gene, and a TRBJ1-4*01 gene.

18. A composition, comprising an engineered immune cell of claim 1 and a pharmaceutically acceptable carrier, diluent, or excipient.

19. An engineered immune cell, comprising a heterologous polynucleotide encoding a binding protein that includes:
(a) a TCR α-chain variable (Vα) domain, wherein the encoded Vα domain
(i)comprises a CDR3 amino acid sequence of SEQ ID NO: 88, and
(ii) has at least about 90% sequence identity to the Vα domain amino acid sequence of SEQ ID NOs: 3 or 98, provided that the encoded Vα domain comprises no change in amino acid sequence of CDR1 and CDR2, and;

(b) a TCR β-chain variable (Vβ) domain, wherein encoded the Vβ domain
(i)comprises a CDR3 amino acid sequence of SEQ ID NO: 14, and
(ii) has at least about 90% sequence identity to the amino acid sequence of SEQ ID NOs: 3 or 98, provided that the encoded Vβ domain comprises no change in amino acid sequence of CDR1 and CDR2,

wherein the encoded binding protein is capable of specifically binding to a peptide containing an HA-1H antigen and does not bind to a peptide that does not contain an HA-1H antigen.

Assignees

• Hutchinson Fred Cancer Res

Inventors

• Bleakley Marie
• Dossa Robson
• Sommermeyer Daniel

Classifications

• C07K14/71

  for growth factors; for growth regulators · CPC title

• C07K2319/40

  containing a tag for immunodetection, or an epitope for immunisation · CPC title

• C12N9/22

  Ribonucleases {[RNase]; Deoxyribonucleases [DNase]} · CPC title

• C12N2510/00

  Genetically modified cells · CPC title

• C07K14/70596

  Molecules with a "CD"-designation not provided for elsewhere · CPC title