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 ICRs 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. A chimeric receptor (MHCR) comprising (i) a class I major histocompatibility complex (MHC) portion, comprised of at least a portion of an extracellular domain of a class I MHC protein, beta2-microglobulin and a targeted peptide, directly fused in the absence of a linker, to a T cell receptor (TCR) portion, comprised of at least an extracellular domain of a TCR, a transmembrane domain of a TCR and at least a portion of a cytoplasmic domain of a TCR protein, wherein the MHCR binds to a TCR of a target cell through the targeted peptide of the MHC portion of the MHCR, or (ii) a class II major histocompatibility complex (MHC) portion, comprised of at least a portion of an extracellular domain of a class II MHC protein and a targeted peptide, directly fused in the absence of a linker, to a T cell receptor (TCR) portion, comprised of at least an extracellular domain of a TCR, a transmembrane domain and at least a portion of a cytoplasmic domain of a TCR protein, wherein the MHCR binds to a TCR of a target cell through the targeted peptide of the MHC portion of the MHCR.
2. The MHCR of claim 1 , wherein binding of the MHCR to the TCR of the target cell initiates a signaling cascade effective for eliminating the target cell.
3. The MHCR of claim 1 , wherein the MHC protein, the TCR protein, or both the MHC protein and the TCR protein are mammalian proteins.
4. The MHCR of claim 1 , wherein the targeted peptide is integrated into the MHC portion, or directly or indirectly fused to the MHC portion.
5. The MHCR of claim 1 , wherein the MHC protein comprises HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, HLA-DRB, H2-Aa, H2-B1, H2-K1, H2-EB beta, H2-EK alpha, H2-EK beta, a fragment thereof, or a combination thereof.
6. The MHCR of claim 1 , wherein the MHC protein comprises HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, HLA-DRB, H2-Aa, H2-B1, H2-K1, H2-EB beta, H2-EK alpha, H2-EK beta, a fragment that is at least 90% identical to HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, HLA-DRB, H2-Aa, H2-B1, H2-K1, H2-EB beta, H2-EK alpha, or H2-EK beta, a fragment thereof, or a combination thereof.
7. The MHCR of claim 1 , wherein the TCR protein comprises TRAC, TRBC1, TRBC2, TRDC, TRGC1, TRGC2, TCRA, TCB1, TCB2, TCC1, TCC2, TCC3, TCC4, a fragment thereof, or a combination thereof.
8. The MHCR of claim 1 , wherein the TCR protein comprises TRAC, TRBC1, TRBC2, TRDC, TRGC1, TRGC2, TCRA, TCB1, TCB2, TCC1, TCC2, TCC3, TCC4, a fragment that is at least 90% identical to TRAC, TRBC1, TRBC2, TRDC, TRGC1, TRGC2, TCRA, TCB1, TCB2, TCC1, TCC2, TCC3, or TCC4, a fragment thereof, or a combination thereof.
9. The MHCR of claim 1 , wherein the MHCR complexes with a CD3 subunit.
10. The MHCR of claim 1 , wherein binding of the MHCR to the TCR of the target cell instructs the target cell to differentiate to a specific effector function.