CD38 Chimeric Co-Stimulating Receptor and Uses Thereof
The presently disclosed subject matter provides uses of a chimeric costimulatory receptor (CCR) targeting CD38, and cells comprising a CD38 CCR and an antigen-recognizing receptor, and uses of such cells.
1 - 100 . (canceled)
101 .- 125 . (canceled)
126 . A cell comprising:
(a) an antigen-recognizing receptor that binds to an antigen; and
(b) a chimeric co-stimulating receptor (CCR) that binds to CD38,
wherein the cell exhibits substantial cytolytic activity against cells that are single positive for the antigen.
127 . The cell of claim 126 , wherein the cell is a cytotoxic T lymphocyte (CTL), a γδ T cell, a tumor-infiltrating lymphocyte (TIL), a regulatory T cell, a Natural Killer T (NKT) cell or a NK cell.
128 . The cell of claim 126 , wherein the antigen-recognizing receptor comprises a T cell receptor (TCR), a TCR like fusion molecule, or a chimeric antigen receptor (CAR).
129 . The cell of claim 126 , wherein the antigen is a tumor antigen or a pathogen antigen.
130 . The cell of claim 126 , wherein the tumor antigen comprises CD19, carbonic anhydrase IX (CAIX), carcinoembryonic antigen (CEA), CD8, CD7, CD10, CD20, CD22, CD30, CD33, CLL1, CD34, CD41, CD44, CD49f, CD56, CD74, CD133, CD138, CD123, CD44V6, an antigen of a cytomegalovirus (CMV) infected cell, epithelial glycoprotein-2 (EGP-2), epithelial glycoprotein-40 (EGP-40), epithelial cell adhesion molecule (EpCAM), receptor tyrosine-protein kinase Erb-B2, Erb-B3, Erb-B4, folate-binding protein (FBP), fetal acetylcholine receptor (AChR), folate receptor-«, Ganglioside G2 (GD2), Ganglioside G3 (GD3), human Epidermal Growth Factor Receptor 2 (HER-2), human telomerase reverse transcriptase (hTERT), Interleukin-13 receptor subunit alpha-2 (IL-13Rα2), κ-light chain, kinase insert domain receptor (KDR), Lewis Y (LeY), L1 cell adhesion molecule (L1CAM), melanoma antigen family A, 1 (MAGE-A1), Mucin 16 (MUC16), Mucin 1 (MUC1), Mesothelin (MSLN), ERBB2, MAGEA3, p53, MART1, GP100, Proteinase3 (PR1), Tyrosinase, Survivin, hTERT, EphA2, NKG2D ligands, cancer-testis antigen NY-ESO-1, oncofetal antigen (h5T4), prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), ROR1, tumor-associated glycoprotein 72 (TAG-72), vascular endothelial growth factor R2 (VEGF-R2), Wilms tumor protein (WT-1), BCMA, GPRC5D, FcRL5, NKCS1, EGF1R, EGFR-VIII, CD99, CD70, ADGRE2, CCR1, LILRB2, PRAME, CD48, P2RY10, CD70, BOB1, CLEC12A, CCR1, LILRB2, CD5, CD38, CS-1, Lewis antigen (LeY), or ERBB.
131 . The cell of claim 128 , wherein the TCR like fusion molecule is a recombinant T cell receptor (TCR) comprising an antigen binding chain that comprises: (a) an antigen-binding fragment of an immunoglobulin variable region that binds to an antigen in an HLA-independent manner; and (b) a constant domain that is capable of associating with a CD3ζ polypeptide.
132 . The cell of claim 131 , wherein the constant domain comprises a native or modified TRAC polypeptide or a native or modified TRBC polypeptide.
133 . The cell of claim 131 , wherein the CD3ζ polypeptide is fused to an intracellular domain of a co-stimulatory molecule or a portion thereof.
134 . The cell of claim 128 , wherein the antigen-recognizing receptor is a CAR, wherein the CAR comprises:
an intracellular CD3ζ signaling domain;
a CD28 co-stimulatory intracellular domain;
a transmembrane domain; and
an extracellular antigen specific binding domain.
135 . The cell of claim 134 , wherein the CD3ζ polypeptide is a native or modified CD3ζ polypeptide.
136 . The cell of claim 135 , wherein the modified CD3ζ polypeptide comprises a native ITAM1, an ITAM2 variant consisting of two loss-of-function mutations, and an ITAM3 variant consisting of two loss-of-function mutations.
137 . The cell of claim 136 , wherein the CCR comprises an extracellular antigen-binding domain that binds to CD38, and an intracellular domain that is capable of delivering a costimulatory signal to the cell but does not alone deliver an activation signal to the cell.
138 . The cell of claim 126 , wherein the intracellular domain of the CCR comprises two or more intracellular domains of a co-stimulatory molecule or a portion thereof.
139 . The cell of claim 133 , wherein the co-stimulatory molecule comprises CD28, 4-1BB, OX40, CD17, CD40, CD154, CD97, CD11a/CD18, ICOS, DAP-10, CD2, CD244, CD27, or NKG2D.
140 . The cell of claim 138 , wherein the co-stimulatory domains are a CD28 co-stimulatory domain and a co-stimulatory 4-1BB intracellular domain.
141 . A method of reducing and/or abolishing expression of CD38 in a cell, comprising introducing into the cell a nucleic acid molecule that encodes a chimeric co-stimulating receptor (CCR) that binds to CD38.
142 . The method of claim 141 , wherein the cell is a T cell, a B cell, a Natural Killer (NK) cell, or a dendritic cell.
143 . A method of treating and/or preventing a disease associated with and/or expressing CD38 in a subject, comprising administering to the subject (a) a CD38 drug and (b) a cell according to claim 126 .
144 . A pharmaceutical composition, comprising the cell according to claim 126 , and a pharmaceutically acceptable carrier.
145 . A method of treating a tumor, comprising the administration of the pharmaceutical composition of claim 144 to a subject.