p95HER2-Targeting CAR with Humanized ScFv for Tumor Specificity
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Solution Overview
Problem
Current cancer treatments, particularly those targeting HER2-positive tumors, face challenges such as drug resistance and cardiotoxicity, and there is a lack of effective therapies specifically targeting the p95HER2 fragment, which is expressed in some HER2-positive tumors but not in healthy tissues, leading to limited adoptive cell therapy options.
Innovation Solution
Development of a chimeric antigen receptor (CAR) that specifically targets p95HER2-expressing cells by using a humanized single-chain variable fragment (ScFv) with a specific arrangement of VH and VL regions, which is capable of inducing potent anti-tumor activity without affecting cells expressing normal levels of HER2, thereby minimizing side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If adoptive cell therapy targets HER2 using conventional CARs, then anti-tumor activity is induced, but cardiotoxicity occurs due to HER2 expression in cardiomyocytes
Solution Approach 1:
The patent applies local quality by engineering the CAR to recognize a specific local variant (p95HER2 fragment) rather than the entire HER2 protein. This localized targeting approach allows the therapy to distinguish between tumor cells expressing the truncated p95HER2 fragment and healthy cardiomyocytes expressing full-length HER2, thereby inducing anti-tumor activity while avoiding cardiotoxicity.
Solution Approach 2:
The invention segments the HER2 antigen recognition by focusing on a specific fragment (p95HER2) rather than the complete HER2 protein. This segmentation enables selective targeting of tumor cells that express the p95HER2 fragment while leaving healthy tissues expressing intact HER2 unaffected, resolving the contradiction between therapeutic efficacy and safety.
2Adaptability or versatility
If CARs target full-length HER2, then broad anti-tumor coverage is achieved, but specificity is reduced due to HER2 expression in healthy tissues
Solution Approach 1:
The patent implements local quality by designing the CAR to recognize a specific local variant (p95HER2 fragment) rather than the entire HER2 protein. This approach maintains adaptability to tumors expressing this fragment while achieving high specificity by excluding healthy tissues that express only full-length HER2.
Solution Approach 2:
Instead of targeting the conventional full-length HER2 antigen, the invention inverts the approach by targeting the alternative p95HER2 fragment. This inversion strategy reverses the selectivity pattern, achieving high tumor specificity by targeting a variant present in tumors but absent in healthy tissues.
3Productivity
If conventional CARs are used against HER2, then T cells can kill tumor cells, but the therapy fails when tumors develop resistance or express normal HER2 levels
Solution Approach 1:
The patent applies inversion by switching from targeting full-length HER2 to targeting the p95HER2 fragment. This strategy overcomes therapy failure in two scenarios: (1) tumors that develop resistance to full-length HER2-targeted therapies, and (2) tumors with normal HER2 expression that lack the p95HER2 fragment, thereby enhancing both killing efficiency and long-term effectiveness.
Data Source
AI summary
The present invention relates to a chimeric antigen receptor (CAR) capable of targeting p95HER2-expressing cells. The invention also relates to a single-chain variable fragment (ScFv), to an antigen-binding domain and to an antibody or antibody fragment thereof capable of binding to the p95HER2 antigen. The invention also relates to a method of cancer diagnosis and to a pharmaceutical composition for use in a method of preventing or treating cancer comprising the CAR and/or the antigen-binding domain or the antibody of the invention.