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T cell receptors and methods of use thereof

A technology of cell receptors and nucleic acid molecules, applied in animal cells, vertebrate cells, genetically modified cells, etc., can solve problems that hinder the comprehensive analysis of anti-tumor T cell specificity

Pending Publication Date: 2022-04-15
UNIV HEALTH NETWORK
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the sheer number of nonmutated antigens and the high polymorphism of HLA genes may have hampered comprehensive analysis of the specificity of antitumor T cell responses to nonmutated antigens

Method used

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  • T cell receptors and methods of use thereof
  • T cell receptors and methods of use thereof
  • T cell receptors and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0235] Example 1 - Method

[0236] cell

[0237] Peripheral mononuclear cells were obtained via density gradient centrifugation (Ficoll-Paque PLUS, GE Healthcare Life Sciences, Marlborough, MA). The K562 cell line is an erythroleukemic cell line with defective HLA class I / II expression. A K562-based artificial APC (aAPC) expressing individual HLA class I genes individually as a single HLA allele in combination with CD80 and CD83 has been previously reported (Butler et al., PloS One 7, e30229 (2012). Jurkat 76 The cell line is a T-cell leukemia cell line lacking expression of endogenous TCR, CD4 and CD8. Jurkat 76 / CD4 cells were produced by retroviral transduction of human CD4 gene. HEK293T cells and melanoma cell lines were supplemented with 10 %FBS and 50 μg / ml gentamicin (Thermo Fisher Scientific, Waltham, MA) in DMEM. K562 and Jurkat 76 cell lines were cultured in RPMI 1640 supplemented with 10% FBS and 50 μg / ml gentamicin .

[0238] peptide

[0239] MAGE-A2 108-127 S...

Embodiment 2

[0259] Example 2 - MAGE-A2 108-127 Characterization of TCR

[0260] from six DP4 + Primary CD4 isolated from a patient with melanoma + T cells were stimulated only once with DP4-aAPC pulsed with peptide fragments (108-127) of MAGE-A2 and cognate DP4 L112W / V141M Dimer staining. To avoid potential in vitro priming, weak stimulation conditions were used. Discovery of MAGE-A2 by dimer staining 108-127 Immunogenic (data not shown).

[0261] In order to verify the dimer staining results, MAGE-A2 was cloned from dimer-positive T cells 108-127 Specific DP4-restricted TCR gene ( Figures 1A-1B and Table 6). when human CD4 + During clonotypic recombination in TCR-deficient T cells, MAGE-A2 108-127 TCR is cognate DP4 L112W / V141M Dimers were successfully stained ( Figures 2A-2D ), and function in a DP4-restricted and antigen-specific manner ( image 3 ).

[0262] TCR 03-MAGE-A2 108-127 Ability to recognize homologous peptides endogenously processed and presented by DP4 ( ...

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Abstract

The present disclosure relates to recombinant T cell receptors capable of binding to MAGE-A2 epitopes and nucleic acid molecules encoding the recombinant T cell receptors. In some aspects, the nucleic acid molecule further comprises a second nucleotide sequence, where the second nucleotide sequence or a polypeptide encoded by the second nucleotide sequence inhibits expression of an endogenous TCR. Other aspects of the disclosure relate to a vector comprising the nucleic acid molecule and a cell comprising the recombinant TCR, the nucleic acid molecule, or the vector. Other aspects of the disclosure relate to methods of using the recombinant TCRs, the nucleic acid molecules, the vectors, and the cells. In some aspects, the methods include treating cancer in a subject in need thereof.

Description

[0001] Cross References to Related Applications [0002] This PCT application claims the benefit of priority to U.S. Provisional Application No. 62 / 880,508, filed July 30, 2019, which is hereby incorporated by reference in its entirety. [0003] References to Sequence Listings Submitted Electronically via EFS-WEB [0004] The contents of the electronically filed Sequence Listing (name: 4285_015PC01_Seqlisting_ST25.txt, size: 23,008 bytes; and date created: July 28, 2020) are hereby incorporated by reference in their entirety. technical field [0005] The present disclosure provides recombinant T cell receptors ("TCRs") that specifically bind human melanoma-associated antigen 2 (MAGE-A2) and uses thereof. [0006] Background of the invention [0007] Immunotherapy has emerged as a key tool in the fight against a variety of diseases, including cancer. T cell therapy is at the forefront of the development of immunotherapeutics, and adoptive transfer of antitumor T cells has be...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/867A61K35/17A61P35/00C07K14/725C12N15/113C12N15/12C12N15/63
CPCA61P35/00C12N15/1138C12N2310/14C12N2320/31C07K14/7051C07K2319/03C07K16/30C07K2317/34C12N5/0636A61K39/4632C12N5/0646A61K39/4611A61K39/464486C12N15/85C12N15/625C12N2510/00C12N2740/10043C12N2740/15043A61P35/04C07K14/5406C07K14/5418C07K14/5425
Inventor 平野直人菅田健二佐生嘉代子
Owner UNIV HEALTH NETWORK
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