Auto/allo-immune defense receptors for the selective targeting of activated pathogenic t cells and nk cells

Abstract

Embodiments of the disclosure concern engineered auto/allo-immune defense receptor (ADR)-expressing T cells that selectively target activated T cells, including pathogenic T cells, to incapacitate them. The chimeric receptors comprise moieties for targeting 4-1BB, OX40, and CD40L, for example, whose expression is indicative of activated T cells. In particular embodiments, there are methods of preventing or treating conditions associated with activated T cells using adoptive T-cell transfer of cells encoding the ADRs.

1 . An isolated polynucleotide, comprising sequence encoding
 a polypeptide, wherein said polypeptide comprises:   (1) one or more of an OX40-specific ligand, a 4-1BB-specific ligand, CD40L-specific ligand, or functional derivatives thereof; that is operably linked to   (2) a signaling domain promoting T-cell activation.   
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . The polynucleotide of  claim 1 , wherein the OX40-specific ligand is OX40L, an antibody that targets OX40, an OX40L-Fc fusion, or a combination thereof. 
     
     
         6 . The polynucleotide of  claim 1 , wherein the 4-1BB-specific ligand is 4-1BBL, an antibody that targets 4-1BB, a 4-1BBL-Fc fusion, or a combination thereof. 
     
     
         7 . The polynucleotide of  claim 1 , wherein the CD40L-specific ligand is CD40, an antibody that targets CD40L, a CD40-Fc fusion, or any other engineered protein capable of specific binding to CD40L. 
     
     
         8 . (canceled) 
     
     
         9 . The polynucleotide of  claim 1 , wherein the polynucleotide further comprises sequence that encodes a spacer between (1) and (2). 
     
     
         10 . The polynucleotide of  claim 9 , wherein the spacer is between 10 and 220 amino acids in length. 
     
     
         11 . The polynucleotide of  claim 10 , wherein the spacer has sequence that facilitates surface detection with an antibody. 
     
     
         12 . The polynucleotide of  claim 11 , wherein the spacer is detectable with an anti-Fc Ab. 
     
     
         13 . The polynucleotide of  claim 12 , wherein the spacer comprises IgG Fc portion. 
     
     
         14 . The polynucleotide of  claim 1 , wherein the polynucleotide further encodes a chimeric antigen receptor, a T-cell receptor, or both. 
     
     
         15 . The polynucleotide of  claim 14 , wherein there is a 2A element or IRES element on the polynucleotide between sequence that encodes the (a) a polypeptide that comprises (1) one or more of an OX40-specific ligand, a 4-1BB-specific ligand, CD40L-specific ligand, or functional derivatives thereof; that is operably linked to (2) a signaling domain promoting T-cell activation and (b) the polynucleotide that encodes the chimeric antigen receptor, a T-cell receptor, or both. 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . The polynucleotide of  claim 1 , wherein the polynucleotide is present in a cell. 
     
     
         21 . (canceled) 
     
     
         22 . The polynucleotide of  claim 20 , wherein the cell is a T cell that comprises one or more chimeric antigen receptors or one or more engineered T cell receptors (TCRs). 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . A polypeptide expressed by a polynucleotide of  claim 1 . 
     
     
         29 . A polypeptide, comprising:
 (1) one or more of an OX40-specific ligand, a 4-1BB-specific ligand, and CD40; that is operably linked to   (2) a signaling domain promoting T-cell activation.   
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . A chimeric receptor-expressing cell, comprising the polynucleotide of  claim 1 . 
     
     
         33 . The cell of  claim 32 , wherein the cell is cell a CAR-transduced T cell or a T cell receptor (TCR)-transduced T cell. 
     
     
         34 . (canceled) 
     
     
         35 . (canceled) 
     
     
         36 . (canceled) 
     
     
         37 . (canceled) 
     
     
         38 . The cell of  claim 32 , wherein the cell is engineered to lack endogenous expression of one or more genes. 
     
     
         39 . The cell of  claim 38 , wherein the cell is engineered to lack endogenous expression of 4-1BB, OX40 and/or CD40L. 
     
     
         40 . (canceled) 
     
     
         41 . (canceled) 
     
     
         42 . A method of preparing cells for cell therapy, comprising the step of transfecting immune effector cells with the polynucleotide of  claim 1 . 
     
     
         43 . (canceled) 
     
     
         44 . The method of  claim 42 , further comprising the step of modifying the cells to express one or more chimeric antigen receptors and/or one or more recombinant T-cell receptors. 
     
     
         45 . The method of  claim 42 , further comprising the step of providing an effective amount of the cells to an individual in need thereof. 
     
     
         46 . (canceled) 
     
     
         47 . A method of treating an individual for a medical condition with allogeneic therapeutic cells, comprising the step of providing to the individual a therapeutically effective amount of allogeneic cells, wherein said cells express a polypeptide comprising (1) one or more of an OX40-specific ligand, a 4-1BB-specific ligand, CD40L-specific ligand, or functional derivatives thereof; that is operably linked to (2) a signaling domain promoting T-cell activation. 
     
     
         48 . (canceled) 
     
     
         49 . The method of  claim 47 , wherein the cells express one or more chimeric antigen receptors and/or one or more recombinant T-cell receptors. 
     
     
         50 . A method of avoiding rejection of allogeneic cells, tissue, or organs in an individual, comprising the step of delivering to the individual an effective amount of allogeneic immune cells expressing an engineered chimeric receptor that comprises an extracellular domain that targets compounds that are selectively present on activated T cells and that comprises CD3 zeta,
 wherein the delivering step results in the following in the individual:   (1) inhibition of endogenous alloreactive T cells in the individual; and/or   (2) suppression of NK cell activation in the individual.   
     
     
         51 . The method of  claim 50 , wherein the allogeneic cells are the allogeneic immune cells expressing the chimeric receptor. 
     
     
         52 . The method of  claim 50 , wherein the allogeneic cells express a chimeric antigen receptor or an engineered T cell receptor. 
     
     
         53 . The method of  claim 50 , wherein the allogeneic immune cells are delivered to the individual before, during, and/or after tissue and/or organ transplantation in the individual. 
     
     
         54 . The method of  claim 50 , wherein the activated T cells are pathogenic T cells. 
     
     
         55 . A method of selectively targeting activated T cells in an individual, comprising the step of providing to the individual an effective amount of immune cells expressing an engineered chimeric receptor, said chimeric receptor comprising:
 (1) an extracellular domain that targets compounds that are selectively present on activated T cells; and   (2) a signaling domain promoting T-cell activation.   
     
     
         56 . (canceled) 
     
     
         57 . The method of  claim 55 , wherein the activated T cells are pathogenic T cells. 
     
     
         58 . A method of preventing or treating a medical condition related to activated T cells in an individual, comprising the step of delivering to the individual an effective amount of immune cells expressing an engineered chimeric receptor that selectively targets said activated T cells, said chimeric receptor comprising:
 (1) an extracellular domain that targets compounds that are selectively present on activated T cells; and   (2) a signaling domain promoting T-cell activation.   
     
     
         59 . (canceled) 
     
     
         60 . The method of  claim 58 , wherein the medical condition is an autoimmune disorder. 
     
     
         61 . The method of  claim 58 , wherein the medical condition comprises graft rejection, graft-versus-host disease, type I diabetes, multiple sclerosis, autoimmune colitis, or a combination thereof. 
     
     
         62 . A method of avoiding NK cell-mediated host rejection of allogeneic T cells, tissues, or organs in an individual, comprising the step of providing to the individual an effective amount of immune cells expressing an engineered chimeric receptor that comprises an extracellular domain that targets compounds that are selectively present on activated T cells and that also comprises a signaling domain promoting T-cell activation. 
     
     
         63 . The method of  claim 62 , wherein the immune cells expressing the engineered chimeric receptor are the allogeneic T cells. 
     
     
         64 . The method of  claim 62 , wherein the immune cells express a chimeric antigen receptor or an engineered T cell receptor. 
     
     
         65 . (canceled) 
     
     
         66 . (canceled) 
     
     
         67 . (canceled) 
     
     
         68 . (canceled)