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Anti-b-cell maturation antigen chimeric antigen receptors with human domains

a technology of chimeric antigen and anti-b-cells, which is applied in the direction of antibody medical ingredients, peptides, fusions for specific cell targeting, etc., can solve the problems of many patients relapse, poor prognosis of many cancers, and many patients relaps

Pending Publication Date: 2020-05-07
UNITED STATES OF AMERICA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides CARs that can reduce or eliminate the potential for anti-CAR immunogenicity, which can limit the effectiveness of CAR therapy. This is achieved by using CARs that have human domains and do not include an artificial linker peptide, an antibody light chain variable region, or an antigen recognition domain that targets more than one antigen. This also improves the persistence of CAR-expressing cells and the effectiveness of CAR therapy.

Problems solved by technology

Despite advances in treatments such as chemotherapy, the prognosis for many cancers may be poor.
For example, therapies for multiple myeloma (MM) may cause remissions, but many patients eventually relapse and die.

Method used

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  • Anti-b-cell maturation antigen chimeric antigen receptors with human domains
  • Anti-b-cell maturation antigen chimeric antigen receptors with human domains
  • Anti-b-cell maturation antigen chimeric antigen receptors with human domains

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0121]This example demonstrates the design of CARs with heavy-chain-only antigen recognition domains.

[0122]Twelve CARs with fully-human heavy-chain-only antigen recognition domains were designed, as shown in FIGS. 1A-1L. The general design of these CARs from the N-terminus to the C-terminus comprises: the CD8α leader sequence, a fully-human heavy chain variable region, the CD8α hinge and transmembrane domains, the cytoplasmic portion of one of 3 costimulatory domains, the cytoplasmic portion of the CD3ζ activation domain. The 3 costimulatory domains tested were CD28, 4-1BB, and inducible T cell costimulatory (ICOS). This example demonstrates the first CARs to be reported with heavy-chain-only antigen recognition domains.

example 2

[0123]This example demonstrates that heavy-chain-only CARs were expressed on the surface of T cells.

[0124]To conduct the experiments, primary human T cells from multiple myeloma (MM) patients were transduced with the heavy-chain-only CARs shown in FIG. 2. CAR surface expression was evaluated by staining the cells with a BCMA-Fc reagent followed by flow cytometry (FIG. 2). All four FHVH CARs were consistently expressed on the surface of T cells as shown in FIG. 2. The median fluorescence intensity of staining was somewhat higher for the 11D5-3-CD828Z control CAR that contained both a light chain variable region and heavy chain variable regions for unknown reasons.

example 3

[0125]This example demonstrates that heavy-chain-only CARs degranulated in a BCMA-specific manner.

[0126]BCMA-specific degranulation of T cells expressing each of the four FHVH CARs shown in FIG. 3 and the 11D5-3-CD828Z CAR were measured. T cells transduced with each of the FHVH CARs upregulated CD107a specifically in response to stimulation with BCMA-expressing target cells but not BCMA-negative target cells as shown in FIG. 3. T cells expressing 11D5-3 also upregulated CD107a (FIG. 3). Upregulation of CD107a demonstrates BCMA-specific degranulation of the T cells, which is part of the perforin-mediated cytotoxicity process.

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Abstract

Provided are chimeric antigen receptors (CARs) having antigen specificity for B-cell Maturation Antigen (BCMA). Also provided are related nucleic acids, recombinant expression vectors, host cells, populations of cells, and pharmaceutical compositions relating to the CARs. Methods of treating or preventing cancer in a mammal are also provided.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This patent application claims the benefit of U.S. Provisional Patent Application No. 62 / 527,556, filed Jun. 30, 2017, which is incorporated by reference in its entirety herein.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with Government support under project number ZIABC01143905 by the National Institutes of Health, National Cancer Institute. The Government has certain rights in the invention.INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ELECTRONICALLY[0003]Incorporated by reference in its entirety herein is a computer-readable nucleotide / amino acid sequence listing submitted concurrently herewith and identified as follows: One 67,061 Byte ASCII (Text) file named “739534_ST25.TXT,” dated Jun. 25, 2018.BACKGROUND OF THE INVENTION[0004]Cancer is a public health concern. Despite advances in treatments such as chemotherapy, the prognosis for many cancers may be poor. For example, therapies fo...

Claims

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Application Information

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IPC IPC(8): A61K35/17C07K14/725C07K14/705
CPCA61K35/17C07K14/70517C07K14/70578C07K14/7051C07K2317/569C07K2317/73C07K14/70521C07K2319/03C07K2319/33C07K2317/21C07K16/2878C07K14/70596A61K2239/48A61K2239/31A61K39/464417A61K39/4631A61K39/4611A61K39/0011A61K2039/5156A61K2039/5158
Inventor KOCHENDERFER, JAMES N.LAM, NORRISTRINKLEIN, NATHANHARRIS, KATHERINE E.ALDRED, SHELLEY FORCEVAN SCHOOTEN, WIM
Owner UNITED STATES OF AMERICA
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