HH1-Derived CAR Design for CD37 Targeting
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Solution Overview
Problem
The design of chimeric antigen receptors (CARs) for targeting CD37-expressing cells is challenging due to unpredictability of antigen binding activity when transitioning from antibody contexts to CAR constructs, and the efficacy can depend on specific domain combinations and configurations.
Innovation Solution
A CAR design utilizing the antigen-binding domain derived from the HH1 antibody, specifically the variable regions and complementarity determining regions (CDRs) of its light and heavy chains, combined with specific hinge, transmembrane, and intracellular signaling domains, is used to create a nucleic acid molecule encoding a CAR capable of binding to CD37 and directing immune effector cells for cytotoxic activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If an antigen-binding domain from an antibody is used in a CAR construct, then the CAR can recognize and bind to the target antigen, but the binding activity is unpredictable when transitioning from antibody context to CAR context
Solution Approach 1:
The patent applies parameter changes by systematically modifying the CAR construct parameters (hinge domain length, transmembrane domain composition, intracellular signaling domain configuration) to optimize antigen binding activity. The HH1-based CAR design iteratively adjusts these parameters to achieve reliable binding while managing design complexity.
Solution Approach 2:
The patent creates a universal CAR platform based on the HH1 antibody that can target multiple CD37-expressing B-cell malignancies. The standardized HH1-CAR design with optimized domain combinations serves as a multi-functional solution applicable across different cancer types expressing the CD37 antigen.
2Adaptability or versatility
If different domain combinations are used in CAR design, then the functionality and efficacy of the CAR may be improved, but the design becomes more complex and difficult to optimize
Solution Approach 1:
The patent segments the CAR construct into distinct functional domains (extracellular antigen-binding domain, hinge domain, transmembrane domain, intracellular signaling domain) that can be independently optimized and recombined. This modular segmentation allows systematic evaluation of different domain combinations without overwhelming complexity.
Solution Approach 2:
The patent systematically varies parameters within each domain (e.g., hinge domain length, signaling domain composition) to identify optimal combinations. The HH1-CAR design employs controlled parameter changes to achieve enhanced functionality while maintaining manageable design complexity through methodical optimization.
3Measurement precision
If a CAR is designed to be highly specific for CD37, then it can effectively target malignant B-cells, but it may have reduced effectiveness against variant antigens or in patients with antigen heterogeneity
Solution Approach 1:
The patent introduces dynamics by combining the highly specific HH1 antigen-binding domain with flexible intracellular signaling domains that can adapt to different cellular contexts. The CAR construct maintains specific CD37 recognition while the signaling components dynamically respond to various activation conditions, enhancing effectiveness against antigen variants.
Solution Approach 2:
The patent creates a composite CAR structure that integrates the HH1 antibody-derived antigen-binding domain with optimized hinge, transmembrane, and signaling domains. This composite design combines the high specificity of HH1 for CD37 with the adaptive capabilities of multiple functional domains, achieving both precise targeting and versatility against antigen variants.
Data Source
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AI summary
The present invention relates to nucleic acid molecules encoding chimeric antigen receptors (CARs) against the antigen CD37. The CARs disclosed herein have complementarity-determining regions (CDRs) derived from the potent monoclonal anti-CD37 antibody HH1, and may be used in immunotherapy to target cells expressing CD37. Such immunotherapy has a particular use in the treatment of B-cell cancers. The CARs of the present invention are highly functional in the redirection of immune cells to kill CD37+ cells, and include humanised CARs of particular use in medical therapy. The present invention also includes vectors comprising the above-described nucleic acid molecules, immune effector cells expressing the aforementioned CARs and the use of such immune effector cells in therapy, particularly adoptive transfer therapy, for cancer, including B-cell malignancies.