Chimeric Antibody Frameworks for Stability and Aggregation Control
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Solution Overview
Problem
Current methods for humanizing non-human antibodies face challenges in achieving high stability and reducing aggregation propensity, which is crucial for therapeutic applications to minimize immunogenicity and production costs.
Innovation Solution
Development of novel chimeric human antibody light chain frameworks comprising framework regions I to III from Vκ and framework region IV from Vλ, with specific sequence selections to enhance stability and reduce aggregation, including mutations at key positions like AHo101.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-human antibodies are used for therapeutic applications, then research and diagnostic effectiveness is improved, but immunogenicity increases leading to immune responses against the therapeutic antibody
Solution Approach 1:
The patent applies local quality by creating chimeric antibodies where only specific regions (variable domains from non-human antibodies) retain the original properties while other regions (constant regions and framework regions) are replaced with human sequences. This localized substitution reduces immunogenicity while preserving therapeutic effectiveness.
Solution Approach 2:
The patent changes the amino acid sequence parameters of the antibody framework regions by replacing non-human sequences with human consensus sequences. This parameter change transforms the antibody from highly immunogenic non-human sequences to less immunogenic human-like sequences while maintaining functional properties.
2Object-affected harmful factors
If humanization approaches are applied to reduce immunogenicity, then immunogenicity is reduced, but stability and aggregation properties may deteriorate
Solution Approach 1:
The patent employs universal human consensus framework sequences that can serve multiple functions: they provide human-like properties to reduce immunogenicity while simultaneously maintaining structural stability and preventing aggregation. The consensus sequences represent optimized human framework regions that fulfill multiple requirements.
Solution Approach 2:
The patent creates composite antibody structures by combining non-human CDR regions (for antigen binding) with human framework and constant regions (for stability and reduced immunogenicity). This composite approach integrates the beneficial properties of both non-human and human antibody regions.
3Object-affected harmful factors
If aggregation is reduced to improve therapeutic properties, then immunogenicity and off-target effects are minimized, but manufacturing complexity may increase
Solution Approach 1:
The patent applies preliminary action by pre-selecting and optimizing human consensus framework sequences before CDR grafting. The framework regions are chosen and engineered in advance to possess inherent stability and low aggregation propensity, preventing these problems before they arise in the final antibody construct.
Solution Approach 2:
The human consensus framework sequences act as intermediaries between the non-human CDR regions and the human constant regions. These framework sequences mediate the interaction by providing a stable, human-like structural context that prevents aggregation while maintaining CDR functionality.
Data Source
AI summary
The present invention relates to novel antibody frameworks with advantageous properties.