Anti-VEGF Monoclonal Antibodies With VEGF165-Selective Binding
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Solution Overview
Problem
Existing anti-VEGF-A antibodies, such as Avastin, have serious toxicities and there is a need for improved safety in targeting VEGF-A, particularly in reducing tumor growth and angiogenesis.
Innovation Solution
Development of monoclonal antibodies with specific heavy and light chain complementarity determining regions (CDRs) that exhibit enhanced affinity for VEGF165, reducing VEGF-A activity by binding differentially to VEGF165 and potentially VEGF121 and VEGF189, thereby inhibiting VEGFR2 phosphorylation and angiogenesis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing anti-VEGF-A antibodies (e.g., Avastin) are used to target VEGF-A, then tumor growth and angiogenesis are inhibited, but serious toxicities and adverse effects occur
Solution Approach 1:
The patent applies local quality by creating antibodies with differential affinity for different VEGF isoforms (VEGF165 vs VEGF121). The antibody selectively targets VEGF165 with high affinity while having reduced affinity for VEGF121, thereby localizing the therapeutic effect to the predominant tumor-associated isoform and reducing off-target effects that cause toxicity.
Solution Approach 2:
The patent changes the binding parameters (affinity and specificity) of the anti-VEGF antibody by engineering specific CDR sequences. The antibody has KD values in the range of 10^-9 to 10^-11 M for VEGF165, providing high-affinity binding, while demonstrating reduced binding to VEGF121, thus altering the pharmacological profile to improve the safety profile.
2Reliability
If anti-VEGF-A antibodies bind to VEGF-A isoforms, then VEGFR2 phosphorylation is inhibited, but binding affinity varies across different VEGF isoforms (VEGF121, VEGF165, VEGF189)
Solution Approach 1:
The patent applies local quality by creating antibodies with differential affinity for different VEGF isoforms (VEGF165 vs VEGF121). The antibody selectively targets VEGF165 with high affinity while having reduced affinity for VEGF121, thereby localizing the therapeutic effect to the predominant tumor-associated isoform and reducing off-target effects that cause toxicity.
Solution Approach 2:
The patent changes the binding parameters (affinity and specificity) of the anti-VEGF antibody by engineering specific CDR sequences. The antibody has KD values in the range of 10^-9 to 10^-11 M for VEGF165, providing high-affinity binding, while demonstrating reduced binding to VEGF121, thus altering the pharmacological profile to improve the safety profile.
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 antibodies demonstrate improved safety and efficacy in reducing tumor growth and angiogenesis by specifically targeting VEGF165, with reduced toxicity compared to existing antibodies.
Implementation Method 1
monoclonal antibody binding to VEGF-A comprising heavy chain complementarity determining regions 1 - 3 (HCDR1, HCDR2, and HCDR3) and light chain complementarity determining regions 1 - 3 (LCDR1, LCDR2, and LCDR3)
Data Source
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AI summary
The present invention relates to antibodies having activity against a vascular endothelial growth factor (VEGF), and methods of making and using such antibodies.