ADGRE2 and CLEC12A Chimeric Receptors for Selective AML Targeting
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Solution Overview
Problem
Current CAR therapies for treating acute myeloid leukemia (AML) face challenges in terms of safety and efficacy due to abundant expression of target antigens in normal hematopoiesis and phenotypic heterogeneity in tumor cells, necessitating a novel combinatorial CAR format with improved safety and efficacy.
Innovation Solution
Development of chimeric receptors targeting ADGRE2 and CLEC12A, comprising specific extracellular antigen-binding domains, transmembrane domains, and intracellular domains, including CD3ζ polypeptides with ITAM mutations, to enhance T cell activation and specificity for AML treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Power
If conventional CAR therapies target abundant antigens in normal hematopoiesis, then T cell activation is enhanced, but off-target toxicity increases
Solution Approach 1:
The patent applies local quality by designing CARs with differential affinity binding characteristics that allow high-affinity binding to tumor cells expressing high levels of target antigens, while low-affinity or no binding to normal cells expressing low levels of the same antigens. This spatially differentiated binding affinity resolves the contradiction between strong T cell activation and reduced off-target toxicity.
Solution Approach 2:
The patent changes the binding affinity parameter of the CAR to create a threshold effect, where the CAR is activated only when target antigen density exceeds a certain threshold (as found on tumor cells) but remains inactive at lower antigen densities (as found on normal cells). This parameter modification enables selective activation and reduces off-target effects.
2Adaptability or versatility
If CAR therapies target phenotypically heterogeneous tumor cells, then broad coverage is achieved, but treatment efficacy decreases
Solution Approach 1:
The patent employs composite CAR designs that combine multiple antigen-binding domains or dual-targeting capabilities within a single CAR construct. This composite structure enables the CAR to recognize and bind to tumor cells with heterogeneous phenotypes by targeting multiple antigens simultaneously or providing redundant recognition pathways, thereby maintaining high treatment efficacy across diverse tumor populations.
3Device complexity
If single-target CAR formats are used, then CAR simplicity is maintained, but therapeutic index deteriorates
Solution Approach 1:
The patent segments the antigen recognition function into multiple independent binding domains within the CAR structure, allowing each domain to target a specific antigen or contribute to affinity maturation. This segmentation enables sophisticated targeting behavior while maintaining a modular CAR architecture that can be systematically constructed and optimized.
Data Source
AI summary
The presently disclosed subject matter provides for chimeric receptors that target ADGRE2 and chimeric receptors that target CLEC12A. The presently disclosed subject matter also provides for cells comprising the ADGRE2-targeted chimeric receptors, cells comprising the CLEC12A-targeted chimeric receptors, and cells comprising the ADGRE2-targeted chimeric receptors and the CLEC12A-targeted chimeric receptors. The presently disclosed subject matter further provides uses of such cells for treating tumors, e.g., AML.