Granted Patent B2

US 12,508,307 · App. 18/515,358 · Granted Dec 30, 2025

Inventors: Yair Reisner (Houston, TX); Noga Or-Geva (Rehovot, IL); Eran Ophir (Rehovot, IL); Yaki Eidelstein (Rehovot, IL); Rotem Gidron Budovsky (Rehovot, IL)

Assignee: Yeda Research and Development Co. Ltd.

A61K39/001A61K39/39566A61K40/11A61K40/31A61K40/32A61K40/42A61K40/4211A61K40/46A61P31/00A61P35/04C07K16/2896C12N5/0636C12N5/0637C12N5/0648A61K2035/122A61K40/50A61K2239/38A61K2239/48A61K2239/57C12N2501/2307C12N2501/2315C12N2501/2321Y02A50/30

Abstract

Claims (30)

1 . A method of generating an isolated cell having a central memory T-lymphocyte (Tcm) phenotype and expressing a heterologous cell surface receptor, said cell being tolerance-inducing cell and capable of homing to the lymph nodes following transplantation, the method comprising:

(a) depleting CD4+ cells or selecting CD8+ cells from peripheral blood mononuclear cells (PBMC);

(b) contacting said cells following step (a) with a third party antigen in the presence of IL-21 so as to allow enrichment of antigen reactive cells;

(c) culturing said cells resulting from step (b) in the presence of IL-21, IL-15 and IL-7 so as to allow proliferation of anti-third party cells comprising said Tcm phenotype; and

(d) transducing said cells during or following said step (b) or (c) with a polynucleotide encoding a cell surface receptor comprising a T cell receptor signaling module and an extracellular domain directed against a disease antigen.

2 . The method of claim 1 , wherein said third party antigen is a viral antigen.

3 . The method of claim 1 , wherein said step (b) is affected for 1-10 days.

4 . The method of claim 1 , wherein said step (c) is affected for 1-15 days.

5 . The method of claim 1 , wherein said step (a) comprises depleting CD56+ cells from said PBMCs.

6 . The method of claim 1 , wherein said method is effected ex-vivo.

7 . The method of claim 1 , wherein said cell surface receptor is a transgenic T cell receptors (tg-TCR).

8 . The method of claim 1 , wherein said cell surface receptor is a chimeric antigen receptor (CAR).

9 . The method of claim 8 , wherein said CAR comprises an antigen binding domain being an antibody or an antigen-binding fragment.

10 . The method of claim 9 , wherein the antigen-binding fragment is a Fab or a scFv.

11 . The method of claim 8 , wherein said CAR comprises a CD32.

12 . The method of claim 8 , wherein said CAR comprises at least one co-stimulatory domain selected from the group consisting of CD28, CD134/OX40, CD137/4-1BB, Lck, ICOS, and DAP10.

13 . The method of claim 8 , wherein said CAR comprises at least two co-stimulatory domains selected from the group consisting of CD28, CD134/OX40, CD137/4-1BB, Lck, ICOS, and DAP10.

14 . The method of claim 1 , wherein said cell surface receptor binds an antigen selected from the group consisting of a tumor antigen, a viral antigen, a bacterial antigen, a fungal antigen, a protozoa antigen, a parasite antigen, an allergic antigen and an autoimmune antigen.

15 . The method of claim 14 , wherein:

said tumor antigen is associated with a solid tumor; or

said tumor antigen is associated with a hematologic malignancy; or

said tumor antigen is selected from the group consisting of CD19, CD20, CD22, ROR1, mesothelin, CD33/IL3Ra, c-Met, PSMA, Glycolipid F77, EGFRvIII, Her2, GD2, gp100, p53, carcinoembryonic antigen (CEA), MART-1, Telomerase reverse transcriptase (TERT), Claudin-6, Receptor tyrosine-protein kinase extracellular domain (ErbB2-ECD), Receptor tyrosine-protein kinase intracellular domain (ErbB2-ICD), Histone H1.2, Histone H4, Tyrosinase, alphafetoprotein (AFP), MAGE A3, AIM-2a, AFP, ART-4, CLCA2, Cyp-B, EphA2, hTERT, iCE, FGF-5, G250, GnT-V, HST-2 (FGF-6), Livin (ML-IAP), MUC1, MUC2, PRAME, PSMA, P15, RAGE, RU1, RU2, SART-1, SART-3, SART-2, SOX10, Survivin, Survivin-2Bg, TRG, Neo-PAP, CAMEL and NY-ESO-1; or

said viral antigen is of a virus selected from the group consisting of human immunodeficiency virus (HIV), T-cell leukemia virus type 1 (TAX), influenza virus, herpes virus, papilloma virus, hepatitis viruses, ebola virus, human T-lymphotropic virus (HTLV), rubella virus, measles virus, rabies virus, lymphocytic choriomeningitis (LCM), rotavirus, mumps virus, adenovirus, and BK polyomavirus (BKV).

16 . The method of claim 1 , wherein said cell is further genetically modified to repress expression of at least one endogenous immunological checkpoint gene in said cell.

17 . The method of claim 1 , further comprising:

(e) separating said cells resulting from step (c) into single cell suspensions; or

selecting for activated cells following step (b) and prior to step (c).

18 . The method of claim 1 , wherein said Tcm phenotype comprises a CD3 + , CD8 + , CD62L + , CD45RA − , CD45RO + signature.

19 . A method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the population of cells generated according to the method of claim 1 , thereby treating the subject.

20 . The method of claim 19 , wherein the disease is selected from the group consisting of a malignant disease, a viral disease, a bacterial disease, a fungal disease, a protozoa disease, a parasite disease, an allergic disease and an autoimmune disease.

Assignments (1)

Continuity (5)

References Cited (369)