HER2-Targeting CH3 Domain Binding Member for Resistant Cancers
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Solution Overview
Problem
Current HER2-specific therapies face challenges with intrinsic or acquired resistance in HER2-positive breast and gastric cancers, necessitating the development of new biomarkers and treatments that can effectively target HER2-positive tumors with high gene copy numbers or mRNA levels.
Innovation Solution
A specific binding member comprising a HER2 antigen binding site engineered into a structural loop region of a CH3 domain, or competing with such a binding member, is used to treat cancers with HER2 gene copy numbers of 10 or higher per tumour cell or high HER2 mRNA levels, offering an alternative therapeutic approach for resistant cases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If trastuzumab and other HER2-specific therapies are used to treat HER2-positive cancers, then treatment efficacy is improved for responsive patients, but intrinsic or acquired resistance develops limiting long-term effectiveness
Solution Approach 1:
The patent applies inversion by using a different molecular approach (Fc fragment with engineered antigen-binding site) compared to conventional full-length antibodies. This structural inversion allows the binding domain to be located in the constant region rather than the variable region, potentially overcoming resistance mechanisms that developed against traditional HER2-targeting antibodies like trastuzumab.
Solution Approach 2:
The patent changes the molecular parameters of the therapeutic agent by using an Fc fragment with engineered antigen-binding sites instead of conventional full-length IgG antibodies. This parameter change in molecular structure and function allows the therapy to potentially overcome resistance while maintaining HER2-targeting efficacy.
2Measurement precision
If HER2 gene copy number and mRNA level testing is implemented to identify responsive patients, then treatment selection accuracy is improved, but diagnostic complexity and cost increase
Solution Approach 1:
The patent applies universality by developing a therapeutic approach (Fc fragment with engineered binding) that can potentially address multiple resistance scenarios and HER2-positive cancer types. The biomarker panel described in the patent also serves multiple functions: patient selection, resistance prediction, and treatment response monitoring, reducing the need for separate diagnostic workflows.
3Adaptability or versatility
If new specific binding members with engineered CH3 domains are developed to overcome resistance, then therapeutic versatility is improved, but manufacturing and validation complexity increases
Solution Approach 1:
The patent applies extraction by isolating and utilizing only the essential functional components (Fc fragment with engineered antigen-binding site in the CH3 domain) while removing or simplifying other parts of the antibody molecule. This extraction approach simplifies manufacturing compared to producing full-length engineered antibodies while retaining the key therapeutic function of HER2 targeting.
Data Source
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AI summary
The invention relates the use of Human Epidermal Growth Factor Receptor 2 (HER2) gene copy number and HER2 mRNA levels as biomarkers to identify cancers which will respond to treatment with a specific binding member comprising a HER2 antigen binding site engineered into a structural loop region of a constant domain, e.g. CH3 domain, of the specific binding member, and specific binding members which compete with such a binding member for binding to HER2.