VEGF Mini-Trap Hinge Engineering for Reduced Immunogenicity
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Solution Overview
Problem
Current VEGF mini-traps used for treating angiogenic eye disorders face challenges due to reactivity with anti-hinge antibodies, leading to immunogenicity and reduced efficacy, and have high systemic exposure and viscosity issues, making them less effective and more uncomfortable for intravitreal administration.
Innovation Solution
Development of VEGF mini-traps with modified hinge regions, such as stealth mutations and protease cleavage sites, to reduce immunogenicity and improve stability and viscosity, allowing for higher concentration formulations and lower volume intravitreal injections, featuring specific amino acid sequences and glycosylation patterns for enhanced efficacy and reduced systemic exposure.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If VEGF mini-traps with standard hinge regions are used, then they can bind to VEGF effectively, but they exhibit high immunogenicity due to reactivity with anti-hinge antibodies
Solution Approach 1:
The patent applies local quality by modifying only the hinge region of the VEGF mini-trap while preserving the VEGF-binding domains. Specific amino acid substitutions (e.g., L352P, L352A, L352G, L352V, L352Q, L352M, L352Y, L352W, L352R, L352K, L352F, L352L, L352I, L352E, L352D, L352N, L352H, L352C, L352S, L352T, L352X, L352Z, L352_) are introduced at position 352 within the hinge region to reduce immunogenicity while maintaining the overall structure and VEGF-binding capability of the mini-trap.
Solution Approach 2:
The patent applies parameter changes by systematically varying the amino acid composition and structure of the hinge region. Different amino acid substitutions at position 352 and other hinge region modifications are tested to optimize the balance between immunogenicity reduction and functional preservation, ultimately selecting the most effective configuration that minimizes anti-hinge antibody reactivity while maintaining VEGF neutralization efficacy.
2Reliability
If VEGF mini-traps are administered at high concentrations, then therapeutic efficacy is improved, but viscosity increases causing injection difficulties and patient discomfort
Solution Approach 1:
The patent applies parameter changes by modifying the physical properties of the VEGF mini-trap through hinge region engineering. The amino acid substitutions and hinge region modifications alter the molecular conformation, intermolecular interactions, and aggregation behavior of the mini-trap, resulting in reduced solution viscosity at high concentrations while preserving therapeutic efficacy. This enables formulation of high-concentration solutions suitable for intravitreal injection.
3Loss of time
If VEGF mini-traps are administered at high concentrations, then dosing frequency can be reduced, but systemic exposure increases
Solution Approach 1:
The patent applies local quality by introducing targeted modifications in the hinge region that specifically affect systemic distribution and clearance without compromising local ocular efficacy. The amino acid substitutions at position 352 and other hinge modifications alter the protein's interaction with systemic clearance mechanisms, reducing systemic exposure while maintaining effective concentrations in the target ocular tissue, thereby enabling extended dosing intervals.
Data Source
AI summary
Vascular endothelial growth factor (VEGF) traps and VEGF mini-traps that include VEGF receptor Ig-like domains, fused to a multimerizing component, are disclosed. The VEGF traps and VEGF mini-traps bind to VEGF and block its interaction with the VEGF receptor. Such molecules are useful for treating angiogenic eye disorders (e.g., age-related macular degeneration), cancer and for other undesired angiogenesis.