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Chimeric antigen receptors (CARs) having mutations in the Fc spacer region and methods for their use

A technology of chimeric antigen receptors and spacers, which can be applied to medical preparations containing active ingredients, drug combinations, antibody medical ingredients, etc., and can solve problems such as inability to impart efficacy to CART cells

Active Publication Date: 2017-08-18
CITY OF HOPE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While these spacer sequences can alleviate FcR binding, their length does not confer optimal efficacy on CAR T cells when targeting certain antigens

Method used

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  • Chimeric antigen receptors (CARs) having mutations in the Fc spacer region and methods for their use
  • Chimeric antigen receptors (CARs) having mutations in the Fc spacer region and methods for their use
  • Chimeric antigen receptors (CARs) having mutations in the Fc spacer region and methods for their use

Examples

Experimental program
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Embodiment 1

[0121] Example 1: Incorporation of a mutated chimeric antigen receptor (CAR) in the IgG4 Fc spacer region avoids Fc receptor-mediated recognition and clearance of CAR T cells, resulting in improved T cell persistence and antitumor efficacy.

[0122] To determine whether cellular FcR-mediated interactions play a role in the immunological rejection and clearance, or even inadvertent activation, of adoptively transferred CAR-expressing T cells, the CH2 domain of the IgG4 Fc spacer of the CD19-specific CAR has been Mutations at one or two sites (L235E and / or N297Q) – referred to herein as CD19R(L235E), CD19R(N297Q) or CD19R(EQ) – and specific for CD19 with a CH2 deletion in its IgG4 Fc spacer CAR - referred to herein as CD19Rch2Δ. T cells expressing these mutated CARs were then compared to those expressing either the non-mutated CAR (CD19R) or only the truncated EGFR as a tracker marker for FcγR binding and CAR-mediated cytolytic activity in vitro, as well as for engraftment and t...

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Abstract

Adoptive immunotherapy using T cells genetically redirected via expression of chimeric antigen receptors (CARs) is a promising approach for cancer treatment. However, this immunotherapy is dependent in part on the optimal molecular design of the CAR, which involves an extracellular ligand-binding domain connected to an intracellular signaling domain by spacer and / or transmembrane sequences.

Description

[0001] priority claim [0002] This application claims priority to US Provisional Patent Application No. 61 / 926,881, filed January 13, 2014, which is hereby incorporated by reference in its entirety, including the drawings. [0003] Statement of Government Interest [0004] This invention was made with Government support under Grant Numbers P50CA107399 and P01CA030206 awarded by the National Institutes of Health (NIH). The government has certain rights in this invention. [0005] Background of the invention [0006] Adoptive immunotherapy using T cells expressing chimeric antigen receptors (CARs) is a promising cancer treatment because these cells can directly recognize and kill antigen-expressing T cells in a human leukocyte antigen (HLA)-independent manner. tumor cells. However, in addition to careful selection of target tumor-associated antigens, this therapeutic approach is highly dependent on optimal molecular design of CARs. [0007] While CARs containing TAA-specific...

Claims

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Application Information

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IPC IPC(8): C07K16/30
CPCC07K14/7051C07K14/70521C07K14/71C07K16/2803C07K16/2866C07K2317/524C07K2317/622C07K2319/00C07K16/00C07K2319/30C07K2319/33C07K16/30C07K2317/53C07K2319/02C07K2319/03A61P35/00A61K2239/38A61K2239/31A61K39/4631A61K39/464412A61K2239/17A61K39/4611A61K2039/5156A61K39/39558A61K45/06C07K14/70517C07K2317/526C07K2317/56C07K2317/92
Inventor 斯蒂芬.J.弗曼克里斯汀.E.布朗尤马马西斯瓦拉劳.约纳拉加达阿门.马蒂罗斯
Owner CITY OF HOPE
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