HER2-Targeted Chimeric Antigen Receptor Design to Reduce Off-Target Toxicity
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Solution Overview
Problem
Existing chimeric antigen receptors (CARs) for targeting solid tumors face challenges in tumor specificity and off-target toxicity due to the expression of tumor antigens on normal tissues, leading to severe toxicities.
Innovation Solution
Development of a chimeric antigen receptor (CAR) with a specific antigen binding domain for HER2, comprising defined CDR sequences and signaling domains, designed to minimize off-target effects by enhancing tumor specificity and reducing normal tissue reactivity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CARs target tumor antigens that are also expressed on normal tissues, then tumor targeting is achieved, but severe toxicities occur to normal tissues
Solution Approach 1:
The patent applies local quality by designing CARs with highly specific antigen binding domains that recognize tumor-specific antigens (such as HER2, GD2, PSA) with high affinity and specificity. The CAR structure includes specialized CDR sequences and signaling domains that create localized immune activation only at tumor sites where the antigen is expressed, thereby achieving effective tumor targeting while minimizing off-target effects on normal tissues.
Solution Approach 2:
The patent utilizes parameter changes by optimizing the affinity and specificity parameters of the antigen binding domain through careful selection and engineering of CDR sequences. By adjusting the binding kinetics and affinity parameters of the CAR against tumor antigens, the system achieves selective activation of immune responses at tumor sites while maintaining low reactivity against normal tissue antigens, thus resolving the contradiction between targeting efficacy and toxicity.
2Object-affected harmful factors
If CARs are designed with high specificity for tumor antigens, then off-target toxicity is reduced, but tumor targeting precision may be compromised
Solution Approach 1:
The patent applies universality by designing modular CAR platforms that can be adapted to target multiple different tumor antigens (such as HER2 in breast cancer, GD2 in neuroblastoma, PSA in prostate cancer) using the same basic CAR architecture. This universal design allows the system to maintain high specificity for each target while preserving the ability to achieve precise tumor targeting across different cancer types, thus resolving the contradiction between specificity and targeting precision.
Solution Approach 2:
The patent incorporates feedback mechanisms through the inclusion of multiple signaling domains in the CAR structure that provide both activation and co-stimulation signals. The signaling domains receive feedback from antigen binding and amplify the immune response selectively at tumor sites, ensuring precise tumor targeting while maintaining high specificity. The feedback loop between antigen recognition and immune activation ensures that only tumor cells with the specific antigen are effectively targeted.
Data Source
AI summary
Provided are chimeric antigen receptors (CAR) specific to a selected tumor antigen. Also provided are structure designs and function profiles of provided CAR candidates.