TMIGD2 CAR Architecture for Durable Tumor Antigen Targeting
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Solution Overview
Problem
Existing CAR-T cell therapies face challenges in overcoming tumor escape mechanisms involving major histocompatibility complexes, and checkpoint inhibition therapies like anti-PD-1/PD-L1 fail to effectively target tumor-associated antigens in many patients.
Innovation Solution
Development of chimeric antigen receptors (CARs) incorporating a TMIGD2 costimulatory domain, which includes an extracellular antigen binding domain, transmembrane region, and intracellular effector domain, to enhance T cell activation and overcome tumor escape mechanisms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CAR-T cell therapies are used, then tumor targeting is achieved, but tumor escape mechanisms involving major histocompatibility complexes reduce therapy effectiveness
Solution Approach 1:
The patent combines multiple functional domains into a single CAR construct: the antigen-binding domain (for tumor targeting), the TMIGD2 costimulatory domain (for enhanced T cell activation and persistence), and the effector domain (for cytotoxic activity). This merging of functions into one integrated receptor allows CAR-T cells to simultaneously recognize tumor antigens, receive strong costimulatory signals, and execute killing functions, thereby overcoming tumor escape mechanisms that target conventional CAR therapies.
Solution Approach 2:
The CAR construct functions as a composite molecular structure integrating different functional elements from various sources. The TMIGD2 costimulatory domain is derived from a specific immune receptor, while the antigen-binding domain can be configured from various antibody fragments. This composite design creates a synergistic effect where each component contributes its specialized function, resulting in enhanced overall therapeutic effectiveness that overcomes tumor resistance mechanisms.
2Reliability
If checkpoint inhibition therapy (anti-PD-1/PD-L1) is used, then immune response is modulated, but tumor-associated antigens are not effectively targeted in many patients
Solution Approach 1:
The CAR construct is segmented into distinct functional modules: the extracellular antigen-binding domain (which can be customized to target specific tumor-associated antigens), the transmembrane domain, and the intracellular signaling domains including TMIGD2. This segmentation allows the antigen-binding domain to be independently optimized for specific tumor targets while the TMIGD2 costimulatory domain provides universal enhanced activation signals, thereby achieving both specific antigen targeting and effective immune response modulation.
3Productivity
If CAR-T cell therapy is administered, then tumor cell killing is enhanced, but functional activity is lost over time due to exhaustion
Solution Approach 1:
The CAR construct is engineered with the TMIGD2 costimulatory domain in advance, which provides preemptive costimulatory signaling that prevents T cell exhaustion before it occurs. This preliminary incorporation of enhanced costimulation mechanisms ensures that CAR-T cells maintain functional activity and proliferative capacity throughout prolonged tumor exposure, rather than becoming exhausted after initial activation.
Data Source
AI summary
The present technology provides chimeric antigen receptors (CARs) comprising a TMIGD2 costimulatory domain. In certain embodiments, these CARs comprise an intracellular region comprising the TMIGD2 costimulatory domain and an effector domain, a transmembrane domain, and an extracellular region comprising an antigen binding domain and, optionally a hinge region and/or leader sequence. In other embodiments, these CARs comprise an intracellular region comprising the TMIGD2 costimulatory domain and an effector domain, a transmembrane domain, and an extracellular region comprising an antigen binding domain which specifically binds to tumor associated antigen B7-H3, and, optionally a hinge region and/or leader sequence. Also provided are nucleic acids, vectors, and cells relating to these CARs, as well as methods of using the CARs, nucleic acids, vectors, and cells in the treatment of conditions associated with expression of specific antigens.