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Methods for identifying activating antigen receptor (ACAR)/inhibitory chimeric antigen receptor (ICAR) pairs for use in cancer therapies

A chimeric antigen receptor, inhibitory technology for the identification of activating antigen receptor (aCAR)/inhibitory chimeric antigen receptor (iCAR) pairs for cancer therapy

Pending Publication Date: 2021-09-28
IMMPACT BIO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0023] In conclusion, there is an urgent need to identify suitable targets for cancer immunotherapy via adoptive transfer of gene-redirected killer cells

Method used

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  • Methods for identifying activating antigen receptor (ACAR)/inhibitory chimeric antigen receptor (ICAR) pairs for use in cancer therapies
  • Methods for identifying activating antigen receptor (ACAR)/inhibitory chimeric antigen receptor (ICAR) pairs for use in cancer therapies
  • Methods for identifying activating antigen receptor (ACAR)/inhibitory chimeric antigen receptor (ICAR) pairs for use in cancer therapies

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0570] vii. Preparation of target cells

[0571] In some embodiments, target cells are prepared and tested in an in vitro system. In some embodiments, an in vitro recombination system will be established for testing the function of the iCAR and / or pCAR constructs in inhibiting aCAR activity against off-target cells. In some embodiments, target cells expressing aCAR epitopes, iCAR epitopes, or both will be generated. In some embodiments, target cells expressing aCAR epitopes, pCAR epitopes, or both will be generated. In some embodiments, recombinant cells expressing aCAR epitopes will represent on-tumor ('on-tumor') cells on target, while cells expressing aCAR and iCAR epitopes will represent on-tumor ('on-tumor') on-target cells. 'off-tumor') healthy cells.

[0572]In some embodiments, the iCAR / aCAR panel will be HLA (including, for example, HLA-A2, HLA-A3, HLA-A, HLA-B, HLA-C, HLA-G, HLA-E, HLA-F, HLA- DPA1, HLA-DQA1, HLA-DQB1, HLA-DQB2, HLA-DRB1 or HLA-DRB5) and CD19. I...

Embodiment 1

[0865] Example 1. LOH rate assessment of HLA genes across cancers

[0866] Introduction:

[0867] A therapeutic strategy is proposed to address the vulnerability caused by genomic loss in cancer cells. The proposed strategy uses a combination of activating CAR T cells (aCAR) and inhibitory CAR T cells (iCAR) to more safely target heterozygous cells that have lost encoding membrane proteins for both maternal and paternal alleles. Tumors with combined genomic segments (i.e., polymorphic protein-coding changes).

[0868] If the target of iCAR is only expressed by non-tumor tissues, iCAR can reduce the off-tumor toxicity of CAR-T therapy without reducing the anti-tumor efficacy. This situation, in which the iCAR target is only expressed by non-tumor cells, occurs when the iCAR antigen is encoded by a part of the genome that has been deleted in tumor cells. One gene family that is highly polymorphic and known to be expressed on all cells is the HLA.

[0869] HLA proteins are al...

Embodiment 2

[0903] Example 2. Genome-wide identification of germline alleles encoding expressed cell surface proteins undergoing loss of heterozygosity

[0904] Introduction:

[0905] If the target of iCAR is only expressed by non-tumor tissues, suppressive CAR-T cells can reduce the off-tumor toxicity of CAR-T therapy without reducing the anti-tumor efficacy. The situation where the iCAR target is only expressed by non-tumor cells is where the iCAR antigen is encoded by a part of the genome that has been deleted in the tumor cells. The goal of this part of the workflow is to identify such alleles.

[0906] Allele Identification:

[0907] We used the Exome Integration Consortium (ExAC) database as input for the analysis (exac.broadinstitute.org). The ExAC database is a compilation of exomes from various population-level sequencing studies, totaling 60,706 exomes 1. ExAC contains information about each variant, including the number of reference allele counts (allele frequency) compare...

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Abstract

The present invention provides a method for identifying a target pair comprising i) an inhibitory chimeric antigen receptor (iCAR) or a protective chimeric antigen receptor (pCAR) capable of preventing or attenuating undesired activation of an effector immune cell, wherein the iCAR or pCAR target is directed to a target extracellular polymorphic epitope, and it) an activating chimeric antigen receptor (aCAR), wherein the aCAR is directed to a target non-polymorphic cell surface epitope of a protein, as well as methods of making and use of such pairs in the treatment of cancer.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Application No. 62 / 738,895, filed September 28, 2018, and U.S. Provisional Application No. 62 / 847,830, filed May 14, 2019, each of which is incorporated herein by reference. [0003] ASCII table [0004] This patent application contains a lengthy tabular section. Copies of these forms are filed concurrently with the corresponding U.S. Patent Application Serial No. 16 / 586,730, filed September 27, 2019, and the provisional application from which the current case claims priority. The ASCII table was created on September 28, 2018 as follows: (1) 120575-5004-PR aCAR_iCAR_pairs_6_27_18Part 1.txt, 66,627,779 bytes, (2) 120575-5004-PR aCAR_iCAR_pairs_6_27_18Part2.txt, 9408,298 bytes (3) 120575-5004-PR candGenes598_AF10_LOH20.txt, 9,310 bytes, (4) 120575-5004-PR extCellAFnLOH1306.txt, 94,814 bytes, (5) 120575-5004-PRonlyExtCell1167genes_no filter.txt, 2, 18 ( )120575-5004-PRon...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/00C12N15/10C12Q1/6886
CPCC07K2317/622C07K2319/03C07K2319/33C12N15/1079C12Q1/6886C12Q2600/156C07K16/2803C07K16/2887C07K16/2827C07K14/7051C07K16/32C07K16/2863C07K2317/24C07K2317/21C07K16/3069A61K39/464406A61K39/464424A61K2239/29A61K39/4631A61K39/4611A61K2239/31A61K39/464404A61K39/464412A61P35/00C07K14/70539C07K16/2833C07K16/28C07K16/3007A61K35/17
Inventor Y·萨吉A·沙比-扬格G·格罗斯W·J·吉布森D·达哈里M·贝曼
Owner IMMPACT BIO LTD
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