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COMPOSITIONS AND METHODS REGARDING ENGINEERED AND NON- ENGINEERED gamma delta-T CELLS FOR TREATMENT OF HEMATOLOGICAL TUMORS

A technology of binding regions and binding domains, applied in chemical instruments and methods, blood/immune system cells, biochemical equipment and methods, etc., can solve uncertain problems

Pending Publication Date: 2021-06-29
APPLIED IMMUNE TECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Notably, the practical translation of any of these various approaches to allogeneic γδ T cells is uncertain at best, given the current lack of understanding of the costimulatory requirements of γδ T cells compared with αβ T cells

Method used

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  • COMPOSITIONS AND METHODS REGARDING ENGINEERED AND NON- ENGINEERED gamma delta-T CELLS FOR TREATMENT OF HEMATOLOGICAL TUMORS
  • COMPOSITIONS AND METHODS REGARDING ENGINEERED AND NON- ENGINEERED gamma delta-T CELLS FOR TREATMENT OF HEMATOLOGICAL TUMORS
  • COMPOSITIONS AND METHODS REGARDING ENGINEERED AND NON- ENGINEERED gamma delta-T CELLS FOR TREATMENT OF HEMATOLOGICAL TUMORS

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0183] In the presence of IL-2 (100 U / mL), 1×10 6 Human PBMC / mL were activated for 5 days in modified cell culture medium on pre-coated anti-Vδ1 antibody D1-08 or D1-35 (see WO 2017 / 197347). On the 5th day, in the presence of fibronectin (retronectin), with coding chimeric antigen receptor (2B7-5.1, SEQ ID NO:11; 3B9-5.1, SEQ ID NO:9; 3H7-5.1, SEQ ID NO:9; 3H7-5.1, SEQ ID NO:9; ID NO: 10; 9C11-5.1, SEQ ID NO: 12) gamma-retroviral construct to transduce cell cultures. On day 6, cells were returned to modified cell culture medium and further expanded with feed and IL-2 replacement as needed. On day 17, 18 or 19, cells were harvested and used A kit (Miltenyi Biotec) was used to deplete remaining αβ T cells. Purity and transduction efficiency of γδ cell populations were assessed by FACS. In parallel, non-transduced cell cultures were expanded in the same manner without addition of retroviral supernatant. Such as image 3 As shown, untransduced expanded Vδ1 cells from multip...

Embodiment 2

[0185] Vδ1 cells were activated, transduced and expanded in the same manner as above. The 3H7 CAR construct SEQ ID NO: 10 was used to demonstrate cytotoxicity against two CD20+ cell lines Daudi and Raji. Such as Figure 4 As shown, the introduction of CAR enhanced the innate cytotoxicity of unengineered Vδ1 cells.

Embodiment 3

[0187] Vδ1 cells were activated, transduced and expanded in the same manner as above. During expansion, four different constructs (SEQ ID NO: 9, 10, 11, 12) were introduced into Vδ1 cells and tested against Raji-Luc cells. Cytotoxicity was determined by total luminescence measurement after addition of the luminescent substrate D-luciferin (Perkin Elmer) after co-incubation for 18 hours at different E / T ratios. Such as Figure 5 As shown, anti-CD20 CAR cells comprising the 4-1BB co-stimulatory endodomain described herein exhibit robust cell killing activity against Raji cells.

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Abstract

Aspects of the invention include compositions and methods for treatment of hematological tumors with engineered or non-engineered gamma delta-T cells. In some embodiments, the gamma delta-T cells comprise a chimeric antigen receptor (CAR) construct. The CAR construct can contain an anti-CD20 binding domain or anti-B cell maturation antigen (BCMA) binding domain, a CD8 hinge and transmembrane domain, a costimulatory domain, a CD3 zeta signalling domain, a combination thereof, or all thereof. The CAR construct can contain a domain encoding for a secreted common gamma chain cytokine such as a sIL15 domain.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 739,822, filed October 1, 2018, the contents of which are incorporated in their entirety for all purposes. [0003] sequence listing [0004] This application contains a Sequence Listing, which was filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on December 17, 2019, is named ADC-0005-PCT_SL.txt and is 147,616 bytes in size. Background technique [0005] Adoptive cell therapy has undergone more than thirty (30 ) years of continuous iteration. While there have been hints and indications along the way of the healing potential of these approaches, much work remains to be done. In particular, whether CAR-T lymphocytes can successfully eradicate tumors depends on the persistence and effector functions of CAR-T cells, but an excess of either of these can trigge...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/00C07K14/54C07K16/28C07K14/725A61K39/395A61P35/00A61P35/02A61K35/17
CPCA61K39/001124A61K39/001112A61K39/001117C07K14/5443C07K16/2887C07K16/2803C07K16/2878C07K2317/73C07K2319/03C07K2317/622C07K14/7051A61K2039/5156A61K39/395A61P35/00A61P35/02A61K35/17C12N2510/00C07K14/70517C07K14/70578C07K2319/33C07K2319/50A61K38/00A61K2300/00C12N15/62C07K14/705C12N5/0636C07K2319/02A61K2039/505A61K38/177A61K38/1774A61K38/2086A61K39/3955A61K2039/5158C07K2317/565C07K2317/74C07K2317/76C07K2319/30
Inventor D.K.萨特帕耶夫M.A.赫尔曼J.M.罗梅罗Y.F.井Z.安A.雅克博维茨
Owner APPLIED IMMUNE TECH LTD
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