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T cell receptor-deficient chimeric antigen receptor t-cells and methods of use thereof

Inactive Publication Date: 2019-02-07
NAT UNIV OF SINGAPORE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a method for stopping the surface receptors in immune cells from showing up. This is done using a tool called a PEBL, which prevents transport of targeted proteins to the cell membrane. By doing this, researchers have been able to modify T cells and make them resistant to graft-versus-host disease, a complication that can occur when using cell-based therapies. The method can also be used to create pharmaceutical compositions that can prevent this complication in patients.

Problems solved by technology

Such PEBL constructs can render T cells transduced with anti-viral TCRs unable to respond to a cognate viral peptide, and can markedly reduce the capacity of human T cells to cause graft-versus-host disease (GvHD).

Method used

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  • T cell receptor-deficient chimeric antigen receptor t-cells and methods of use thereof
  • T cell receptor-deficient chimeric antigen receptor t-cells and methods of use thereof
  • T cell receptor-deficient chimeric antigen receptor t-cells and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

embodiment 1

[0167]An engineered CD3 / TCRαβ-negative T cell comprising a polypeptide comprising a target-binding molecule linked to a localizing domain, wherein the target-binding molecule comprises an antibody that binds a CD3 / TCRαβ complex protein, wherein the localizing domain comprises a retention signaling domain comprising an amino acid sequence selected from the group consisting of an endoplasmic reticulum (ER) retention sequence, a Golgi retention sequence, and a proteosome localizing sequence, and wherein the target-binding molecule linked to the localizing domain is not secreted by the engineered cell.

embodiment 2

[0168]The engineered T cell of embodiment 1, wherein the CD3 / TCRαβ complex protein is selected from the group consisting of TCRα, TCRβ, CD3ε, CD3δ, CD3γ, and CD3ζ.

embodiment 3

[0169]The engineered immune cell of embodiment 1 or 2, wherein the antibody is a single chain variable fragment (scFv).

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Abstract

The present invention provides compositions comprising a protein expression blocker or PEBL comprising a target-binding molecule and localizing domain, and methods of using such compositions in cancer therapy. PEBLs are useful as a blockade of expression of target surface receptors (peptides or antigens) in immune cells. Also provided herein are CD3 / TCRαβ-deficient T cells and CD3 / TCRαβ-deficient chimeric antigen receptor T cells that express such PEBLs.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims benefit to U.S. Provisional Application No. 62 / 543,735 filed Aug. 10, 2017, the disclosure in its entirety is herein incorporated by reference.REFERENCE TO A SEQUENCE LISTING[0002]The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Aug. 9, 2018, is named “119419-5003-US01-SequenceListing_ST25.txt” and is 24.0 kilobytes in size.BACKGROUND OF THE INVENTION[0003]Genetically-engineered immune cells are a powerful new treatment for cancer. Results of recent clinical trials with T lymphocytes expressing chimeric antigen receptors (CARs) have provided compelling demonstration of the power of this approach. Chimeric antigen receptors (CARs) can redirect immune cells to specifically recognize and kill tumor cells. CARs are artificial multi-molecular proteins constituted by a single-cha...

Claims

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Application Information

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IPC IPC(8): A61K39/00C07K16/28A61P35/02
CPCA61K39/001111A61K39/001112C07K16/2809C07K16/2803A61P35/02A61K2039/5156C07K2319/02C07K2319/04C07K2317/56A61K2039/505C07K2317/622C07K2319/03C07K2319/32C07K2319/33A61P37/06C12N15/62C07K14/7051C12N5/0636A61K2239/38A61K39/4632A61K2239/48A61K39/4621A61K2239/26A61K2239/31A61K39/46434A61K39/464411A61K39/4631A61K39/464838A61K39/464412A61K39/4611A61K35/17A61K39/0008A61K39/001A61K2035/122A61K2039/5158
Inventor CAMPANA, DARIOKAMIYA, TAKAHIRO
Owner NAT UNIV OF SINGAPORE
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