HER3 Binding Polypeptides for Tumor Penetration
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Solution Overview
Problem
Current therapies targeting the HER3 receptor in cancers face challenges due to its low expression on tumor cells and the poor tissue distribution and penetration of large antibody molecules, leading to inefficient therapeutic and imaging outcomes.
Innovation Solution
Development of novel HER3 binding polypeptides with high affinity, derived from a three-helical bundle scaffold, which bind to HER3 with a dissociation constant of at most 1 x 10^-9 M, enabling improved targeting and retention in tumors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If large antibody molecules are used to target HER3, then therapeutic effect is achieved, but tissue distribution and penetration capacity deteriorate
Solution Approach 1:
The invention extracts the essential HER3-binding function from the complete antibody molecule, utilizing only the binding domain (such as scFv or Fab fragments) rather than the full antibody structure. This extraction maintains therapeutic efficacy while eliminating the size-related penetration barriers.
Solution Approach 2:
The patent creates simplified copies of the antibody's HER3-binding functionality using smaller molecular formats such as single-chain variable fragments (scFv) and Fab fragments. These copies replicate the target-specific binding capability without the cumbersome size of intact antibodies, thereby improving tissue penetration while preserving therapeutic effect.
2Reliability
If large antibody molecules are used for targeting, then HER3 binding is achieved, but tumor penetration rate deteriorates
Solution Approach 1:
The invention employs short-lived, rapidly penetrating molecular formats such as scFv and Fab fragments that can quickly traverse tumor tissue. These smaller molecules serve as disposable delivery vehicles that penetrate efficiently and can be administered repeatedly without the long circulation times and slow penetration characteristics of full-sized antibodies.
3Reliability
If full-length monoclonal antibodies are used, then therapeutic effect is achieved, but molecular imaging contrast deteriorates
Solution Approach 1:
For molecular imaging applications, the invention extracts only the essential binding and imaging functions from full-length antibodies, using smaller fragments that clear rapidly from blood while maintaining tumor targeting. This extraction achieves high tumor-to-blood contrast ratios necessary for precise imaging while preserving the ability to deliver therapeutic effect.
Solution Approach 2:
The patent creates imaging-optimized copies using smaller antibody fragments that replicate tumor-targeting capability but exhibit superior pharmacokinetic properties for imaging. These copies clear faster from circulation, producing higher contrast images while maintaining the ability to bind HER3 and deliver therapeutic payload.
Data Source
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AI summary
The present disclosure relates to polypeptides which bind to human epidermal growth factor receptor 3 (HER3) and to use of such polypeptides in imaging and therapy. The disclosure provides an HER3 binding polypeptide comprising a HER3 binding motif, which motif consists of the amino acid sequence EKYX4AYX7EIW X11LPNLTX17X18QX20AAFIGX26LX28D