PDGFRβ Binding Polypeptides Isoform Specificity
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Solution Overview
Problem
There is a need for novel PDGFR antagonists that can effectively treat diseases associated with PDGFR activation, as existing solutions are inadequate in addressing the pathologies mediated by platelet-derived growth factor receptors.
Innovation Solution
Development of isolated binding polypeptides with specific VH/VL pairs that bind to human PDGFRβ with high affinity, inhibiting receptor activation and activity, particularly for treating age-related macular degeneration and other PDGFRβ-associated diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing PDGFR antagonists are used, then treatment of PDGFR-associated diseases is attempted, but they are inadequate in effectively addressing pathologies mediated by PDGFR activation
Solution Approach 1:
The patent develops binding polypeptides with specific VH/VL pair configurations that are locally optimized to recognize and bind to the PDGFRβ isoform with high specificity. The variable heavy (VH) and variable light (VL) domain sequences are engineered to match the unique epitope structure of PDGFRβ, distinguishing it from other PDGFR isoforms and achieving isoform-specific antagonism.
Solution Approach 2:
The invention modifies the binding parameters of the polypeptides by optimizing the amino acid sequences in the VH and VL domains. Specific changes in the complementarity determining regions (CDRs) of these domains alter the binding affinity and specificity, enabling the polypeptides to effectively antagonize PDGFRβ with picomolar affinity while maintaining stability.
2Reliability
If binding polypeptides with high affinity are developed, then receptor activation is effectively inhibited, but the complexity of designing specific VH/VL pairs increases
Solution Approach 1:
The binding polypeptide is segmented into distinct variable heavy (VH) and variable light (VL) domain components. Each domain contains specific complementarity determining regions (CDRs) that can be independently optimized. This segmentation allows for systematic design and screening of VH/VL pairs to achieve high affinity binding while managing design complexity through modular approaches.
3Adaptability or versatility
If specific VH/VL pairs are designed for PDGFRβ, then isoform-specific antagonism is achieved, but the scope of applicability to other PDGFR isoforms is limited
Solution Approach 1:
Instead of designing a broad-spectrum antagonist that targets all PDGFR isoforms, the invention inverts the approach by creating an isoform-specific antagonist that targets only PDGFRβ. This selective approach uses carefully engineered VH/VL pairs that recognize unique structural features of PDGFRβ, achieving high specificity by focusing on a single isoform rather than attempting universal coverage.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The binding polypeptides specifically target PDGFRβ, offering high affinity and efficacy in inhibiting receptor activation, providing a potential therapeutic solution for diseases like age-related macular degeneration and cancer by antagonizing PDGFRβ activity.
Implementation Method 1
an isolated binding polypeptide comprising a stable VH/VL pair that specifically binds to human platelet-derived growth factor receptor beta (PDGFRβ)
Data Source
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AI summary
The present invention provides binding polypeptides (e.g., antibodies or fragments thereof) that specifically bind to a target antigen (e.g., a human antigen, e.g., human PDGFRβ) with high affinity. The invention also provides, libraries of binding polypeptides, pharmaceutical compositions, as well as nucleic acids encoding binding polypeptides, recombinant expression vectors and host cells for making such binding polypeptides. Methods of using binding polypeptide of the invention to diagnose and treat disease are also encompassed by the invention.