Ankyrin Repeat Binding Proteins Selecting VEGF-A165
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Solution Overview
Problem
Current anti-VEGF therapies for cancer and eye diseases such as AMD or DME are not effective for all patients and can cause cytotoxic side effects due to their inability to distinguish between pro- and anti-angiogenic forms of VEGF-A, leading to inhibition of both angiogenesis and essential survival factors.
Innovation Solution
Development of recombinant binding proteins with ankyrin repeat domains that specifically bind to VEGF-A165 with high affinity, inhibiting its binding to VEGFR-2 and thereby targeting the pro-angiogenic form of VEGF-A without affecting the anti-angiogenic form, using specific sequence motifs like 1D23G4TPLHLAA56GHLEIVEVLLK7GADVNA.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current anti-VEGF therapies are used to inhibit VEGF-A signaling, then angiogenesis is inhibited, but both pro-angiogenic and anti-angiogenic forms of VEGF-A are blocked causing cytotoxic side effects
Solution Approach 1:
The binding protein is designed with specific local properties to distinguish between different VEGF-A isoforms. The ankyrin repeat domain contains specific amino acid residues at key positions that create a binding interface selectively recognizing the pro-angiogenic VEGF-A165 conformation, while not binding to the anti-angiogenic VEGF-A165b isoform that has a different C-terminal structure. This local specificity in binding allows selective inhibition of pathological angiogenesis without blocking protective anti-angiogenic forms.
Solution Approach 2:
The invention changes the binding parameters of the therapeutic agent by using a non-antibody binding protein with distinct binding characteristics. The ankyrin repeat domain exhibits different binding affinity and specificity parameters compared to conventional anti-VEGF antibodies, enabling selective recognition of VEGF-A165 based on subtle conformational differences between isoforms, thereby achieving isoform-selective inhibition.
2Reliability
If current anti-VEGF therapies are used, then tumor growth is inhibited, but therapeutic specificity is insufficient to distinguish between VEGF-A isoforms
Solution Approach 1:
The binding protein incorporates specific local structural features in the ankyrin repeat domain, particularly at residues 1-8, that create a highly specific binding interface for VEGF-A165. This local structural precision allows the protein to recognize and bind only to the pro-angiogenic isoform while leaving the anti-angiogenic isoform unaffected, thereby achieving high therapeutic specificity.
3Reliability
If broad-spectrum anti-VEGF therapy is applied, then all VEGF-A mediated pathways are blocked, but essential survival factors are also inhibited
Solution Approach 1:
The invention exploits the structural differences between VEGF-A isoforms, particularly the C-terminal variations, to convert the previously harmful lack of specificity into a beneficial selective binding property. The ankyrin repeat domain is designed to recognize specific structural features of VEGF-A165 that are absent in the anti-angiogenic isoforms, thereby transforming the broad-spectrum inhibition approach into a selective therapy that spares protective factors.
Data Source
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AI summary
The present invention relates to binding proteins specific for VEGF-A, in particular to recombinant binding proteins comprising a binding domain, which inhibits VEGF-Axxx binding to VEGFR-2. Examples of such binding proteins are proteins which comprise an ankyrin repeat domain with the desired binding specificity. The binding proteins are useful in the treatment of cancer and other pathological conditions, e.g. eye diseases such as age-related macular degeneration.