REDIRECTED CELLS WITH MHC CHIMERIC RECEPTORS AND METHODS OF USE IN IMMUNOTHERAPY
Chimeric receptors featuring major histocompatibility molecules grafted onto T cell receptor molecules and surrogate co-receptors featuring cell surface receptor ligands fused with signaling molecule domains. The chimeric receptors can be used to redirect cells, altering their specificity. T cells expressing chimeric receptors may bind to TCRs of target T cells for which their chimeric receptors are specific. Surrogate co-receptors may be used to help enhance TCR-CD3 signaling as part of this modular receptor system. The chimeric receptors and surrogate coreceptors may be used to help eliminate autoreactive T cells or program T cells to desired effector functions.
1 . An engineered cell, comprising:
a. A chimeric receptor module (MHCR) that comprises: i) an extracellular domain of a major histocompatibility complex (MHC); ii) a T-cell receptor (TCR) portion comprising a transmembrane domain of a TCR, and a cytoplasmic domain of a TCR; and
b. A surrogate coreceptor (SCR) that comprises: i) an extracellular region of a cell surface receptor ligand; ii) a transmembrane region; and iii) a kinase.
2 . The engineered cell of claim 1 , wherein the extracellular domain of the MHC is directly bound to the TCR portion.
3 . The engineered cell of claim 1 , wherein an antigenic peptide is bound to the extracellular domain of the MHC.
4 . The engineered cell of claim 1 , wherein the extracellular domain of the MHC is derived from an MHC selected from the group consisting of: HLA-A, HLA-B, HLA-C, Beta2-microglobulin, HLA-DPA, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, HLA-DRB, H2-Aa, H2-B1, H2-K1, H2-EB beta, H2-EK alpha, and H2-EK beta.
5 . The engineered cell of claim 1 , wherein the transmembrane domain and the cytoplasmic domain of the TCR are derived from a TCR selected from the group consisting of: TRAC, TRBC1, TRBC2, TRDC, TRGC1, and TRGC2.
6 . The engineered cell of claim 1 , wherein the cell surface receptor ligand is a T-cell surface receptor ligand.
7 . The engineered cell of claim 1 , wherein the T-cell surface receptor ligand is selected from the group consisting of: a CD28 ligand, a CTLA-4 ligand, an ICOS ligand, an OX40 ligand, and a CD2 ligand.
8 . The engineered cell of claim 1 , wherein the T-cell surface receptor ligand is selected from the group consisting of: CD80 and CD86.
9 . The engineered cell of claim 1 , wherein the kinase is a Src kinase.
10 . The engineered cell of claim 9 , wherein said Src kinase is Lck or Fyn.
11 . The engineered cell of claim 6 , wherein the T-cell surface ligand is CD80, and the kinase is Lck.
12 . The engineered cell of claim 6 , wherein the T-cell surface ligand is CD86, and the kinase is Lck.
13 . The engineered cell of claim 1 , wherein said engineered cell is a T cell, NK cell, or NK T cell.