Bispecific CAR-T Cells Targeting CD269 and CD38
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Solution Overview
Problem
Current CAR-T cell therapies face challenges in specificity and persistence due to off-target effects and immune responses, particularly when using mouse-derived antibodies, which can lead to relapse in cancer treatments like multiple myeloma, and there is a need for improved targeting of BCMA and CD38 antigens in multiple myeloma cells.
Innovation Solution
Development of a bispecific chimeric antigen receptor (CAR) modified T lymphocytes that specifically target CD269 and CD38 antigens, with a linker peptide and co-stimulatory signaling domains to enhance affinity and persistence, using human-derived antibodies to minimize immune rejection and improve treatment efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mouse-derived antibodies are used in CAR-T cells to target tumor antigens, then the CAR-T cells can recognize and bind tumor cells, but off-target effects occur leading to immune responses against normal tissues and cell relapse
Solution Approach 1:
The patent changes the origin parameter of the antibody from mouse-derived to human-derived (humanized antibody sequences), which fundamentally alters the immunogenicity profile. This parameter change eliminates off-target immune responses while preserving tumor antigen recognition capability, directly resolving the contradiction between reliability and harmful effects
Solution Approach 2:
The patent applies local quality by using human-derived antibody sequences specifically in the antigen-binding regions (CDR grafting) while maintaining the overall CAR structure. This localized modification of antibody origin in critical binding regions improves specificity without compromising the overall function of the CAR-T cell
2Reliability
If single-specific CAR-T cells targeting one antigen are used, then the design is simple, but the targeting precision is insufficient and relapse occurs
Solution Approach 1:
The patent merges two separate antigen-specific binding regions (anti-BCMA and anti-CD38) into a single chimeric antigen receptor molecule. This combining of multiple specificities in one CAR structure improves targeting precision by requiring dual antigen presence for activation, while the merged structure is more manageable than separate CARs
Solution Approach 2:
The patent creates a universal CAR structure that can simultaneously recognize two different tumor antigens (BCMA and CD38) through its dual scFv domains. This multi-functional design allows one CAR-T cell population to target multiple antigens, improving precision without requiring multiple separate CAR-T cell products
Data Source
AI summary
The embodiments of the present invention provide a bispecific chimeric antigen receptor, consisting of a signal peptide, two specific antigen-binding fragments, an extracellular spacer region, a transmembrane region, an intracellular co-stimulatory signaling domain, the first antigen that is recognized and bound by the specific antigen-binding fragments is a member selected from the group consisting of CD19, CD20, CD22, CD33, CD269, CD138, CD79a, CD79b, CD23, ROR1, CD30, B cell surface antibody light chain, CD44, CD123, Lewis Y, CD7 and CD46; the second antigen that is recognized and bound by the specific antigen-binding fragments is CD38, the two specific antigen-binding fragments is linked by a linker peptide, the bispecific chimeric antigen receptor can recognize respectively two kinds of tumor-associated antigens by constructing low affinity chimeric antigen receptors and high affinity chimeric antigen receptors and have very strong specificity. In addition, the embodiments of the present invention also provide a use of the bispecific chimeric antigen receptor in the treatment of tumors.