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Use of the cd2 signaling domain in second-generation chimeric antigen receptors

A chimeric antigen receptor, signal transduction technology, applied in the field of ICOS, lymphocyte function-related resistance, can solve problems such as quantitative and qualitative differences

Inactive Publication Date: 2014-11-05
THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Ligation of the native CD2 molecule has been shown to result in quantitative and qualitative differences compared to TCR-induced calcium signaling

Method used

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  • Use of the cd2 signaling domain in second-generation chimeric antigen receptors
  • Use of the cd2 signaling domain in second-generation chimeric antigen receptors
  • Use of the cd2 signaling domain in second-generation chimeric antigen receptors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0255] Example 1: Use of the CD2 Signaling Domain in Second Generation Chimeric Antigen Receptors

[0256] Incorporation of co-stimulatory domains into chimeric antigen receptors increases cytokine production and target cell killing. CD2 is a co-stimulatory molecule that can affect calcium-mediated signaling. Here it was examined whether inclusion of the CD2 intracellular domain in the CAR affects calcium influx / signaling and cytokine production.

[0257] The materials and methods used in these experiments are now described.

[0258] CD2-containing CAR

[0259] Cloning of the CD2 co-stimulatory domain into various CD19 or mesothelin-specific CARs. E.g, figure 1 The nucleotide sequence of the anti-CD19-CD2z CAR is shown (SEQ ID NO: 1).

[0260] T cells

[0261] Blood samples were obtained from the Human Immunology Core at the University of Pennsylvania. Using RosetteSep kit (stem cell technology), peripheral blood CD4 + and CD8 + T cell negative isolation. Cells...

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Abstract

The present invention provides compositions and methods for treating cancer in a human. The invention includes relates to administering a genetically modified T cell expressing a CAR having an antigen binding domain, a transmembrane domain, a CD2 signaling domain, and a CD3 zeta signaling domain. The invention also includes incorporating CD2 into the CAR to alter the cytokine production of CAR-T cells in both negative and positive directions.

Description

[0001] Related Application Cross Reference [0002] This application claims priority to US Provisional Application Serial No. 61 / 601,907, filed February 22, 2012, the entire contents of which are incorporated herein by reference. Background of the invention [0003] Chimeric antigen receptor (CAR)-modified T lymphocytes with a CD3-ζ signaling domain exhibited moderate levels of target tumor cell lysis and low levels of cytokine production. The binding of costimulatory signaling domains, usually CD28 or 4‐1BB, to second-generation CARs significantly enhanced target cell killing and cytokine production. Ligation of native CD2 molecules has been shown to result in quantitative and qualitative differences compared to TCR-induced calcium signaling. Recent reports demonstrated that ligation of the endogenous CD2 receptor significantly enhanced IL-2 production from first-generation CAR-T cells. [0004] Available data suggest that CAR T cells need to engraft and survive in patients...

Claims

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Application Information

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IPC IPC(8): C07K14/705
CPCC07K14/7051C07K14/705C07K14/70507C07K2319/00A61K2239/48A61K39/4611A61K39/4631A61K2239/21A61K39/464412A61K39/464468C07K16/2803C07K16/30C07K2319/02A61P35/00A61P37/04A61P43/00C12N15/85
Inventor C·H·琼J·朔勒A·D·波西
Owner THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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