Recombinant Binding Proteins with Dual HER2 and Albumin Targeting
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Solution Overview
Problem
Recombinant binding proteins comprising designed ankyrin repeat domains typically exhibit fast pharmacokinetic clearance and short terminal half-lives, and existing methods to improve stability, such as using a single designed ankyrin repeat domain with binding specificity for serum albumin, are not sufficient for clinical drug candidates, while dual targeting of HER2 is required for superior anti-tumor efficacy but is challenging due to the complexity of optimizing domain selection and structural arrangement.
Innovation Solution
A recombinant binding protein comprising four designed ankyrin repeat domains, with two domains specifically binding to HER2 and two to serum albumin, exhibiting improved storage stability and pharmacokinetic properties, is developed, where the two serum albumin-binding domains enhance the protein's stability and half-life, and the HER2-binding domains are optimized for dual targeting.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If a single designed ankyrin repeat domain with binding specificity for serum albumin is used to improve pharmacokinetic properties, then the terminal half-life is extended, but the storage stability is insufficient for clinical drug candidates
Solution Approach 1:
The protein is divided into multiple functional domains: two designed ankyrin repeat domains bind to serum albumin to extend half-life, while two other domains bind to HER2 for anti-tumor activity. This segmentation allows each domain to specialize in a specific function without compromising the other.
Solution Approach 2:
The recombinant binding protein is a composite molecule combining multiple designed ankyrin repeat domains with different binding specificities (serum albumin and HER2). This composite structure integrates the pharmacokinetic benefits of serum albumin binding with the therapeutic anti-tumor activity against HER2-positive cancers.
2Reliability
If dual targeting of HER2 is implemented for superior anti-tumor efficacy, then the anti-tumor activity is enhanced, but the complexity of optimizing domain selection and structural arrangement increases
Solution Approach 1:
The designed ankyrin repeat protein scaffold serves multiple functions simultaneously: it provides the structural framework for binding to both serum albumin (for pharmacokinetic extension) and HER2 (for anti-tumor activity). This multi-functionality reduces the need for separate protein components and simplifies the overall system.
Solution Approach 2:
The patent optimizes specific parameters of the designed ankyrin repeat domains, including their sequence, structure, and spatial arrangement, to achieve the desired binding affinities and pharmacokinetic properties. By carefully adjusting these parameters, the complex multi-domain protein achieves superior anti-tumor efficacy while maintaining manageable complexity in its design and optimization.
Data Source
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AI summary
New recombinant binding proteins, comprising designed ankyrin repeat domains with binding specificity for HER2, and comprising designed ankyrin repeat domains with binding specificity for serum albumin, are disclosed, as well as nucleic acids encoding such recombinant binding proteins, pharmaceutical compositions comprising such recombinant binding proteins or nucleic acids and the use of such recombinant binding proteins, nucleic acids or pharmaceutical compositions in the treatment of diseases.