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