Recombinant CAR Gene CD137 CD3zeta T Cell Proliferation
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Solution Overview
Problem
Current CAR-T cell therapy for cancer, particularly in CD30-positive tumors like Hodgkin's Lymphoma and anaplastic large cell lymphoma, faces limitations due to incomplete replication of the multi-stranded TCR signal complex by the intracytoplasmatic scFv-TCRζ domain, leading to suboptimal T cell function and proliferation.
Innovation Solution
A recombinant CAR gene is developed, incorporating an antigen-binding portion of the CD30 antibody, a transmembrane portion, and cytoplasmic functional regions of CD137 and CD3zeta, which are linked in various orders, to enhance T cell specificity and proliferation for targeted killing of CD30-positive tumor cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If the intracytoplasmatic scFv-TCRζ domain is used in CAR-T cell therapy, then the T cell can recognize tumor antigens in a non-MHC restricted manner, but the signal cannot fully replicate the multi-stranded TCR signal complex, leading to suboptimal T cell function and proliferation
Solution Approach 1:
The patent combines multiple cytoplasmic domains (CD28, CD137, and CD3ζ) into a single CAR construct to merge multiple signaling functions. This merging allows the CAR to replicate the complex multi-stranded TCR signal complex more effectively, thereby improving T cell proliferation and function while maintaining non-MHC restricted antigen recognition capability
Solution Approach 2:
The CAR construct uses a composite structure combining different functional domains from various immune receptors (antigen-binding scFv, transmembrane domain, and composite cytoplasmic signaling domains). This composite design enables the single CAR molecule to perform multiple signaling functions that would normally require multiple separate molecules, resolving the contradiction between simplified structure and complex signal replication
2Device complexity
If a simple scFv-TCRζ CAR structure is used, then the gene structure is relatively simple and easy to construct, but the transfection efficiency and proliferation capability of T lymphocytes are insufficient
Solution Approach 1:
The patent merges multiple cytoplasmic domains (CD28, CD137, CD3ζ) into a unified CAR construct, creating a more complex but functionally superior structure. This merging of domains directly addresses the productivity issue by enhancing T cell proliferation capability and transfection efficiency, while the modular nature of the construction maintains reasonable complexity
3Quantity of substance
If the CAR-T cells are expanded in large amounts in vitro, then there are sufficient cells for infusion, but the transfection efficiency and proliferation capability remain suboptimal
Solution Approach 1:
The patent changes the structural parameters of the CAR gene by incorporating multiple cytoplasmic domains (CD28, CD137, CD3ζ) with different signaling functions. This parameter change in the molecular structure leads to improved transfection efficiency and enhanced proliferation capability, which in turn enables more effective production of sufficient CAR-T cell quantities for clinical infusion
Data Source
AI summary
The invention provides a recombinant chimeric antigen receptor (CAR) gene, a vector containing the same, a CAR-T cell and a use thereof. The recombinant CAR gene comprises a nucleic acid sequence encoding an antigen-binding portion of a CD30 antibody, a transmembrane portion and a CD137 cytoplasmic functional region and a CD3zeta cytoplasmic functional region linked in any order; also provides a method of treating Hodgkin's lymphoma or anaplastic large cell lymphoma or other CD30-positive tumors using the CAR-T cells of the invention.