Tcrs specific for minor histocompatibility (h) antigen ha-1 and uses thereof

Abstract

The present disclosure provides compositions and methods for targeting a minor histocompatibility (H) antigen (HA-1H) 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 .- 26 . (canceled) 
     
     
         27 . A method for treating or for preventing a relapse of a hyperproliferative disorder characterized by expression of an HA-1 H  antigen in a subject, the method comprising administering to the subject 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 the HA-1 H  antigen and does not bind to a peptide that does not contain the HA-1 H  antigen.   
     
     
         28 . The method of  claim 27 , wherein the encoded binding protein of the engineered immune cell is capable of specifically binding to a HA-1 H  peptide:HLA complex. 
     
     
         29 . The method of  claim 28 , wherein the HLA comprises HLA-A*0201. 
     
     
         30 . The method of  claim 27 , wherein the engineered immune cell further comprises 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.   
     
     
         31 . The method of  claim 27 , wherein
 the encoded Vβ domain of the engineered immune cell has at least 90% identity to the amino acid sequence of SEQ ID NO: 3 or 98, and the encoded Vα domain of the engineered immune cell has at least 90% identity to the amino acid sequence of SEQ ID NO:4 or 99.   
     
     
         32 . The method of  claim 31 , wherein
 the encoded Vβ domain of the engineered immune cell comprises the amino acid sequence of SEQ ID NO: 3 or 98, and the encoded Vα domain of the engineered immune cell comprises the amino acid sequence of SEQ ID NO: 4 or 99.   
     
     
         33 . The engineered immune cell of  claim 27 , wherein the encoded binding protein of the engineered immune cell comprises a TCR α-chain having at least 90% identity to the amino acid sequence of SEQ ID NO: 30 or 111. 
     
     
         34 . The method of  claim 27 , wherein the encoded binding protein of the engineered immune cell comprises a TCR β-chain having at least 90% identity to the amino acid sequence of SEQ ID NO: 29 or 110. 
     
     
         35 . The method of  claim 27 , wherein the encoded binding protein of the engineered immune cell comprises:
 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.   
     
     
         36 . The method of  claim 35 , wherein the (i) heterologous polynucleotide encoding the TCR α-chain of the engineered immune cell and the (ii) heterologous polynucleotide encoding the TCR β-chain of the engineered immune cell 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). 
     
     
         37 . The method of  claim 36 , wherein the encoded binding protein of the engineered immune cell comprises the amino acid sequence of SEQ ID NO:54. 
     
     
         38 . A method for treating or for preventing a relapse of a hyperproliferative disorder characterized by expression of an HA-1 H  antigen in a subject, the method comprising administering to the subject an engineered immune cell, comprising a heterologous transgene polynucleotide comprising or consisting of the nucleotide sequence of SEQ ID NO: 85. 
     
     
         39 . The method of  claim 27 , wherein the immune cell is a T cell, a NK cell, or a NK-T cell. 
     
     
         40 . The method of  claim 27 , wherein the peptide containing the HA-1 H  antigen comprises the amino acid sequence VLHDDLLEA (SEQ ID NO:66). 
     
     
         41 . The method of  claim 27 , wherein the Vα domain of the engineered immune cell comprises an amino acid sequence encoded by a TRAV21 gene, and the Vβ domain of the engineered immune cell comprises an amino acid sequence encoded by a TRBV7-9 gene. 
     
     
         42 . The method of  claim 41 , wherein the TRAV21 gene comprises TRAV21*02 and the TRBV7-9 gene comprises TRB7*03. 
     
     
         43 . The method of  claim 41 , wherein the heterologous polynucleotide encoding a binding protein further comprises a TRAJ40*01 gene, a TRBD1*01 gene, and a TRBJ1-4*01 gene. 
     
     
         44 . The method of  claim 27 , wherein the engineered immune cell is administered to the subject as a composition comprising the engineered immune cell and a pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
         45 . A method for treating or for preventing a relapse of a hyperproliferative disorder characterized by expression of an HA-1 H  antigen in a subject, the method comprising administering to the subject 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 NO:4 or 99, 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 the HA-1 H  antigen and does not bind to a peptide that does not contain the HA-1 H  antigen.   
     
     
         46 . The method of  claim 27 , wherein the hyperproliferative disorder comprises a hematological malignancy; wherein the hematological malignancy optionally comprises a leukemia, a lymphoma, a myelodysplastic disorder, or a myeloma. 
     
     
         47 . The method of  claim 46 , wherein the hematological malignancy comprises
 (A) a leukemia selected from acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), mixed phenotype acute leukemia (MPAL), chronic myeloid leukemia (CML), B cell prolymphocytic leukemia, hairy cell leukemia, or chronic lymphocytic leukemia (CLL),   (B) a lymphoma is selected from Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), a central nervous system lymphoma, small lymphocytic lymphoma (SLL), CD37+ dendritic cell lymphoma, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, extra-nodal marginal zone B-cell lymphoma of mucosa-associated (MALT) lymphoid tissue, nodal marginal zone B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, precursor B-lymphoblastic lymphoma, immunoblastic large cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, or Burkitt's lymphoma; or   (C) a myelodysplastic disorder selected from refractory cytopenia with unilineage dysplasia (refractory anemia, refractory neutropenia, and refractory thrombocytopenia), refractory anemia with ring sideroblasts (RARS), refractory anemia with ring sideroblasts—thrombocytosis (RARS-t), refractory cytopenia with multinieage dysplasia (RCMD), refractory cytopenia with multinieage dysplasia and ring sideroblasts (RCMD-RS), refractory anemia with excess blasts (RAEB), myelodysplasia unclassifiable, or refractory cytopenia of childhood.   
     
     
         48 . The method of  claim 27 , wherein the subject is receiving or previously received a hematopoietic cell transplant (HCT) a lymphodepleting chemotherapy, or both a hematopoietic cell transplant (HCT) and a lymphodepleting chemotherapy. 
     
     
         49 . The method of  claim 48 , wherein the HCT comprises a donor hematopoieitic cell comprising a chromosomal knockout of a gene that encodes an HLA component, a chromosomal knockout of a gene that encodes a TCR component, or both. 
     
     
         50 . The method of  claim 48 , wherein the lymphodepleting chemotherapy comprised cyclophosphamide, fludarabine, anti-thymocyte globulin, or a combination thereof. 
     
     
         51 . The method of  claim 27 , wherein the engineered cell is allogeneic to the subject. 
     
     
         52 . The method of  claim 38 , wherein the hyperproliferative disorder comprises a hematological malignancy; wherein the hematological malignancy optionally comprises a leukemia, a lymphoma, a myelodysplastic disorder, or a myeloma. 
     
     
         53 . The method of  claim 52 , wherein the hematological malignancy comprises
 (A) a leukemia selected from acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), mixed phenotype acute leukemia (MPAL), chronic myeloid leukemia (CML), B cell prolymphocytic leukemia, hairy cell leukemia, or chronic lymphocytic leukemia (CLL),   (B) a lymphoma is selected from Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), a central nervous system lymphoma, small lymphocytic lymphoma (SLL), CD37+ dendritic cell lymphoma, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, extra-nodal marginal zone B-cell lymphoma of mucosa-associated (MALT) lymphoid tissue, nodal marginal zone B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, precursor B-lymphoblastic lymphoma, immunoblastic large cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, or Burkitt's lymphoma; or   (C) a myelodysplastic disorder selected from refractory cytopenia with unilineage dysplasia (refractory anemia, refractory neutropenia, and refractory thrombocytopenia), refractory anemia with ring sideroblasts (RARS), refractory anemia with ring sideroblasts—thrombocytosis (RARS-t), refractory cytopenia with multinieage dysplasia (RCMD), refractory cytopenia with multinieage dysplasia and ring sideroblasts (RCMD-RS), refractory anemia with excess blasts (RAEB), myelodysplasia unclassifiable, or refractory cytopenia of childhood.   
     
     
         54 . The method of  claim 38 , wherein the subject is receiving or previously received a hematopoietic cell transplant (HCT) a lymphodepleting chemotherapy, or both a hematopoietic cell transplant (HCT) and a lymphodepleting chemotherapy. 
     
     
         55 . The method of  claim 54 , wherein the HCT comprises a donor hematopoieitic cell comprising a chromosomal knockout of a gene that encodes an HLA component, a chromosomal knockout of a gene that encodes a TCR component, or both. 
     
     
         56 . The method of  claim 54 , wherein the lymphodepleting chemotherapy comprised cyclophosphamide, fludarabine, anti-thymocyte globulin, or a combination thereof. 
     
     
         57 . The method of  claim 38 , wherein the engineered cell is allogeneic to the subject. 
     
     
         58 . The method of  claim 38 , wherein the method comprises administering to the subject a composition comprising a plurality of the engineered immune cell, wherein at least about 30% of the engineered immune cells in the composition are CD4 +  T cells and at least about 30% of the engineered immune cells in the composition are CD8 +  T cells, wherein the engineered CD4+ T cells and the engineered CD8+ T cells are present in about a 1:1 ratio in the composition, and wherein the composition contains substantially no naïve T cells. 
     
     
         59 . The method of  claim 38 , further comprising administering to the subject a cognate compound of the encoded iCasp9 or the encoded RQR8 in an amount effective to ablate in the subject the previously administered engineered immune cell. 
     
     
         60 . The method of  claim 59 , wherein the cognate compound is AP1903. 
     
     
         61 . The method according to  claim 58 , wherein the cognate compound is rituximab.