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Immune cells expressing chimeric antigen receptor

A chimeric antigen receptor and cell technology, applied in the field of immunotherapy, can solve the unsatisfied problems of multiple myeloma treatment improvement

Pending Publication Date: 2020-10-23
THE GENERAL HOSPITAL CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, there is an unmet need for improved treatments for multiple myeloma

Method used

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  • Immune cells expressing chimeric antigen receptor
  • Immune cells expressing chimeric antigen receptor
  • Immune cells expressing chimeric antigen receptor

Examples

Experimental program
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Embodiment approach

[0344] 1. A chimeric antigen receptor (CAR) polypeptide comprising:

[0345] a) two or more extracellular domains each comprising a tumor necrosis factor (TNF) superfamily receptor ligand or a portion thereof;

[0346] b) a transmembrane domain; and

[0347] c) Intracellular signaling domain.

[0348] 2. The CAR polypeptide of paragraph 1, wherein the transmembrane domain comprises a hinge / transmembrane domain.

[0349] 3. The CAR polypeptide of paragraph 1 or 2, further comprising one or more co-stimulatory domains.

[0350] 4. The CAR polypeptide of any of paragraphs 1-3, wherein the TNF superfamily receptor ligand is a proliferation-inducing ligand (APRIL).

[0351] 5. The CAR polypeptide according to any one of paragraphs 1-3, wherein the TNF superfamily receptor ligand is TNF-α, lymphotoxin β, OX40 ligand (OX40L), CD154, Fas ligand (FasL ), LIGHT, TNF-like ligand 1A (TL1A), CD70, Siva, CD153, 4-1BB ligand (4-1BBL), TNF-related apoptosis-inducing ligand (TRAIL), nuclea...

Embodiment 1

[0518] Embodiment 1. Design of chimeric antigen receptor (CAR) based on APRIL

[0519]Described herein are chimeric antigen receptors, which are cells based on APRIL (proliferation-inducing ligand) fused to the transmembrane domain of CD8 or 4-1BB and the signaling domain of the T-cell activating receptors CD3ζ, CD3n, or CD3θ ectodomain. These CARs can overcome resistance to anti-BCMA-targeted therapies and utilize dimerization and trimerization transmembrane domains for optimal function. These CARs are considered for the treatment of cancer (eg, multiple myeloma), plasma cell disorders, and / or severe autoimmune diseases.

[0520] The inventors contemplate that natural ligands for BCMA can be used to engineer antigen-binding moieties to generate anti-myeloma CAR T cells. The cytotoxic activity, antigen-specific proliferation, and cytokine production of scFv-based and natural ligand (APRIL)-based CART cells in myeloma cell lines expressing BCMA, TACI, and / or BAFF receptors we...

Embodiment 2

[0535] Example 2. Limiting antigen escape in multiple myeloma by dual antigen targeting

[0536] Despite recent advances in treatment, multiple myeloma remains an incurable disease. Several recent clinical trials of CAR T cells targeting B-cell maturation antigen (BCMA) have resulted in clinical responses, including complete remissions in patients with multiple myeloma. However, treatment failure due to antigenic loss of BCMA has been described in some patients. The transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) is thought to have a redundant role for BCMA in maintaining plasma cell survival and is also highly expressed in multiple myeloma cells. In the work described here, APRIL, the natural ligand of BCMA and TACI, was used as the CAR binding moiety. The approach prevents disease relapse due to antigen escape by dual targeting multiple surface antigens in multiple myeloma ( image 3 ).

[0537] Materials and methods

[0538] CAR c...

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Abstract

Described herein are methods for producing and utilizing T cells comprising chimeric antigen receptors (CAR) comprising two or more extracellular domains, each comprising a portion of the extracellular domain of a Tumor Necrosis Factor (TNF) superfamily receptor ligand, e.g., A PRoliferation-Inducing Ligand (APRIL). The CARs described herein are capable of targeting, e.g., B cell maturation antigen (BCMA) and / or transmembrane activator and CAML interactor (TACI). Additionally, the CAR T cells of the present invention overcome resistance to anti-BCMA targeted therapies and utilize dimerizing and trimerizing transmembrane domains for optimal function. Further, the invention is related to methods of treating cancer (e.g., multiple myeloma (MM)), plasma cell diseases or disorders, autoimmunediseases or disorders, or transplant rejection.

Description

[0001] Cross References to Related Applications [0002] This application claims International Patent Application No. PCT / US2018 / 013221, filed January 10, 2018, and U.S. Provisional Application No. 62 / 629,558, filed February 12, 2018, U.S. Provisional Application No., filed November 27, 2018 62 / 771,998 and the benefit of U.S. Provisional Application No. 62 / 773,001, filed November 29, 2018, the contents of which are hereby incorporated by reference in their entirety. technical field [0003] The techniques described herein relate to immunotherapy. [0004] sequence listing [0005] This application contains a Sequence Listing filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on January 10, 2018, is named 51295-012WO4_Sequence_Listing_1.10.19_ST25 and is 83,402 bytes in size. Background technique [0006] Chimeric antigen receptors (CARs) provide a means of directing cytotoxic T-cell responses to target ce...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/00C07K14/475C07K14/525C07K14/725
CPCA61K38/00C07K14/7051C07K2319/03C07K2319/33A61K2039/804C07K2319/02C07K2319/74A61K2039/585C07K14/70575C07K14/70517C07K14/70521C07K14/70578C07K16/2878C07K2319/735A61K39/4631A61K2239/31A61K39/4611A61K2239/38A61K2239/48A61K39/464438A61K39/464417A61P35/00A61K35/17C07K2317/622
Inventor M·V·莫斯B·崔
Owner THE GENERAL HOSPITAL CORP
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