Single Domain Antibody VEGFA Binding Topical Delivery
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Solution Overview
Problem
Current anti-VEGF therapies face challenges in developing humanized and stabilized antibody domains for topical delivery in ophthalmology and creating multi-valent and multi-specific molecules due to size and stability issues, limiting their effectiveness in treating conditions like ocular diseases.
Innovation Solution
Development of humanized, stabilized single domain antibodies targeting VEGFA with high affinity, capable of blocking VEGF-VEGFR interaction, which can be used as building blocks for generating multivalent and multi-specific molecules, such as a bivalent anti-VEGFA molecule by tandem fusion of VH domain antibodies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Length of moving object
If conventional antibody therapies are used, then VEGF targeting is achieved, but the molecules are too large for effective topical delivery in ophthalmology
Solution Approach 1:
The patent applies segmentation by using single domain antibody (VHH) molecules instead of full-length antibodies. These VHH domains are approximately 15-20 kDa, representing just the variable region of a full antibody, thereby reducing size while maintaining VEGF binding capability through preserved complementarity-determining regions (CDRs).
Solution Approach 2:
The patent extracts only the essential functional components needed for VEGF binding - specifically the variable domains containing the CDRs - while removing the Fc regions and constant regions that contribute to bulk size. This extraction maintains the core binding function while enabling topical delivery.
2Length of moving object
If antibody domains are made smaller for topical delivery, then delivery capability improves, but structural stability may be compromised
Solution Approach 1:
The patent applies parameter changes by stabilizing the VHH domain structure through specific amino acid substitutions and consensus sequence optimization. Framework region (FR) sequences are designed to maintain proper folding and structural integrity despite the reduced size, ensuring the domain remains stable in the reduced immunoglobulin fold configuration.
Solution Approach 2:
The patent creates a composite structural design where the VHH domain combines stabilized framework regions with functional CDRs, forming an integrated unit that maintains both small size and structural stability. The domain is designed to function as a self-contained modular unit that can be fused to other proteins or antibodies.
3Adaptability or versatility
If single domain antibodies are used, then modularity and fusion capability improve, but binding affinity may be reduced compared to full antibodies
Solution Approach 1:
The patent applies universality by designing VHH domains that can serve multiple functions: they bind VEGF with high affinity, maintain structural stability, and can be fused to various proteins or antibody fragments. The standardized FR sequences enable consistent folding and reliable integration into different molecular constructs, whether used alone or in multivalent arrangements.
Solution Approach 2:
The patent uses partial action by employing single domain antibodies that bind VEGF with sufficient affinity for therapeutic effect, even though full antibodies typically provide higher affinity through two binding domains. The VHH domains are designed to compensate for this partial binding capacity through optimized CDR sequences and structural stabilization.
Data Source
AI summary
VEGFA-binding molecules are disclosed. Also disclosed are nucleic acids and expression vectors encoding, compositions comprising, and methods using, the VEGFA-binding molecules.