Chimeric antigen receptors

Abstract

Provided herein are therapeutic polypeptides, e.g., chimeric antigen receptors, able to direct an immune cell, e.g., a T lymphocyte to a target antigen, and able to cause the T cell to proliferate or to kill cells displaying the antigen when the antigen binds to the polypeptide, wherein the polypeptides comprise a transmembrane domain from a T cell co-inhibitory protein such as CTLA4 or PD-1. Also provided herein are T lymphocytes expressing the polypeptides, and use of such T lymphocytes to treat diseases such as cancer.

1 - 80 . (canceled) 
     
     
         81 . A polypeptide comprising (i) a transmembrane domain from an immune system protein that transmits an inhibitory signal to immune cells, (ii) an intracellular signaling domain that transmits a primary activation signal to immune cells, and (iii) an extracellular domain that binds to an antigen, wherein the intracellular signaling domain and the extracellular domain of said polypeptide are not from the immune system protein. 
     
     
         82 . The polypeptide of  claim 81 , wherein said polypeptide is a chimeric antigen receptor (CAR). 
     
     
         83 . The polypeptide of  claim 81 , wherein the immune system protein is PD-1 or CTLA4. 
     
     
         84 . The polypeptide of  claim 81 , wherein the immune system protein is PD-1, and the transmembrane domain is or comprises the polypeptide sequence of any of SEQ ID NO:6-8. 
     
     
         85 . The polypeptide of  claim 81 , wherein the immune system protein is CTLA4. 
     
     
         86 . The polypeptide of  claim 85 , wherein the transmembrane domain from CTLA4 is or comprises the polypeptide sequence of any of SEQ ID NO:1-5. 
     
     
         87 . The polypeptide of  claim 81 , wherein said extracellular domain is or comprises (i) an antibody or an antigen-binding portion thereof or (ii) a receptor or a portion of a receptor that binds to said antigen. 
     
     
         88 . The polypeptide of  claim 81 , wherein said antigen is an antigen on a tumor cell. 
     
     
         89 . The polypeptide of  claim 81 , wherein said antigen is Her2, prostate stem cell antigen (PSCA), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen-125 (CA-125), CA19-9, calretinin, MUC-1, epithelial membrane protein (EMA), epithelial tumor antigen (ETA), tyrosinase, melanoma-associated antigen (MAGE), CD34, CD45, CD99, CD117, chromogranin, cytokeratin, desmin, glial fibrillary acidic protein (GFAP), gross cystic disease fluid protein (GCDFP-15), HMB-45 antigen, protein melan-A (melanoma antigen recognized by T lymphocytes; MART-1), myo-D1, muscle-specific actin (MSA), neurofilament, neuron-specific enolase (NSE), placental alkaline phosphatase, synaptophysis, thyroglobulin, thyroid transcription factor-1, the dimeric form of the pyruvate kinase isoenzyme type M2 (tumor M2-PK), CD19, CD22, CD27, CD30, CD70, GD2 (ganglioside G2), EGFRvIII (epidermal growth factor variant III), sperm protein 17 (Sp17), mesothelin, PAP (prostatic acid phosphatase), prostein, TARP (T cell receptor gamma alternate reading frame protein), Trp-p8, STEAP1 (six-transmembrane epithelial antigen of the prostate 1), an abnormal ras protein, an abnormal p53 protein, integrin αvβ3 (CD61), galactin, K-Ras (V-Ki-ras2 Kirsten rat sarcoma viral oncogene), or Ral-B. 
     
     
         90 . The polypeptide of  claim 81 , wherein said intracellular signaling domain (i) is a CD3ζ intracellular signaling domain or (ii) is from a lymphocyte receptor chain, a TCR/CD3ζ complex protein, an Fc receptor subunit, or an IL-2 receptor subunit. 
     
     
         91 . The polypeptide of  claim 81 , wherein said polypeptide further comprises one or more co-stimulatory domains, wherein the one or more co-stimulatory domains are not from the immune system protein. 
     
     
         92 . The polypeptide of  claim 91 , wherein said one or more co-stimulatory domains comprise one or more of a co-stimulatory CD27 polypeptide sequence, a co-stimulatory CD28 polypeptide sequence, a co-stimulatory OX40 (CD134) polypeptide sequence, a co-stimulatory 4-1BB (CD137) polypeptide sequence, and a co-stimulatory inducible T-cell costimulatory (ICOS) polypeptide sequence. 
     
     
         93 . The polypeptide of  claim 81 , wherein said polypeptide further comprises a co-stimulatory domain comprising a co-stimulatory 4-1BB (CD137) polypeptide sequence. 
     
     
         94 . The polypeptide of  claim 81 , wherein said extracellular domain is joined to said transmembrane domain by a spacer polypeptide sequence. 
     
     
         95 . The polypeptide of  claim 94 , wherein the spacer polypeptide sequence comprises (i) a CH2CH3 hinge polypeptide sequence or (ii) a hinge polypeptide sequence from CD8, CD28, CTLA4, or PD-1. 
     
     
         96 . A nucleic acid sequence encoding the polypeptide of  claim 81 . 
     
     
         97 . A modified immune cell comprising the polypeptide of  claim 81 . 
     
     
         98 . The modified immune cell of  claim 97 , wherein the modified immune cell is a modified T lymphocyte. 
     
     
         99 . A pharmaceutical composition comprising the modified immune cell of  claim 97 , wherein the modified immune cell is formulated in a pharmaceutically acceptable solution. 
     
     
         100 . A method of treating an individual having a disease or disorder, comprising administering to the individual the modified immune cell of  claim 97 .