T cell receptors and methods of use thereof

A cell receptor, cell cycle technology, applied in animal cells, vertebrate cells, chemical instruments and methods, etc., can solve problems such as hindering the comprehensive analysis of anti-tumor T cell specificity

Pending Publication Date: 2022-05-27
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

[0231] Example 1 - Method

[0232] cell

[0233] Peripheral mononuclear cells were obtained via density gradient centrifugation (Ficoll-Paque PLUS, GE Healthcare Life Sciences, Marlborough, MA). The K562 cell line is an erythroleukemia cell line with deficient HLA class I / II expression. K562-based artificial APCs (aAPCs) expressing various HLA class I genes individually as a single HLA allele in combination with CD80 and CD83 have been previously reported (Butler et al., PloS One 7, e30229 (2012). Jurkat 76 Cell lines were T-cell leukemia cell lines lacking expression of endogenous TCR, CD4 and CD8. Jurkat 76 / CD4 cells were generated by retroviral transduction of the 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 grown in RPMI 1640 supplemented with 10% FBS and 50 μg / ml gentamicin .

[0234] Peptide

[0235] CCND 1219-238 Synt...

Embodiment 2

[0257] Example 2 - CCND1 219-238 Characterization of TCRs

[0258] From six DP4 + Primary CD4 isolated from melanoma patients + T cells were stimulated only once with DP4-aAPCs pulsed with peptide fragments (219-238) of CCND1 and the cognate DP4 L112W / V141M Dimer staining. To avoid potential in vitro priming, weak stimulation conditions were used. Discovery of CCND1 by dimer staining 219-238 Immunogenic (data not shown).

[0259] To validate the dimer staining results, we cloned CCND1 from dimer-positive T cells. 219-238 DP4-restricted TCR gene with specificity ( Figures 1A-1B and Table 6) when in human CD4 + CCND1 during clonotype recombination in TCR-deficient T cells 219-238 TCR is homologous to DP4 L112W / V141M The dimer was successfully stained ( Figures 2A-2D ), and function in a DP4-restricted and antigen-specific manner ( image 3 ).

[0260] TCR 03-CCND1 219-238 Homologous peptides that are endogenously processed and presented by DP4 can be recognized ...

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Abstract

The present disclosure relates to recombinant T cell receptors capable of binding to CCND1 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-REFERENCE TO RELATED APPLICATIONS [0002] This PCT application claims the benefit of priority from US Provisional Application No. 62 / 880,504, filed July 30, 2019, which is incorporated herein 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: 4285-013PC01_SL_ST25.txt, size: 22,576 bytes; and date of creation: July 28, 2020) are incorporated herein by reference in their entirety. technical field [0005] The present disclosure provides recombinant T cell receptors ("TCRs") that specifically bind human G1 / S-specific cyclin-D1 (CCND1) 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 been shown to i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/867A61K35/17A61P35/00C07K14/725
CPCA61P35/00A61K35/17C12N15/86C12N2740/13043C07K14/7051A61K39/0011C07K16/18C12N15/1138C12N5/0636C07K16/2809C07K2317/33C07K2317/622C07K2317/31C12N2740/10043A61P35/04C07K14/5406C07K14/5418C07K14/5425C07K14/55C07K16/30C07K2319/03
Inventor 平野直人菅田健二佐生嘉代子
Owner UNIV HEALTH NETWORK
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