Anti-C-MET Antibody Humanization Balancing Affinity and Immunogenicity
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Solution Overview
Problem
Current anti-C-MET antibodies face challenges in maintaining target binding specificity, affinity, and stability due to inefficient humanization processes, leading to potential immunogenicity and high manufacturing costs, and there is a need for improved antibodies that can effectively block C-MET signaling and engage immune cells.
Innovation Solution
Development of anti-C-MET antibodies with specific heavy and light chain variable regions, engineered through a method involving grafting CDRs from non-human sources into human frameworks, followed by phage library screening and mutagenesis to enhance humanization and minimize immunogenicity, while maintaining binding affinity to both human and cynomolgus monkey C-MET.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If CDR grafting and back mutations are used to humanize antibodies, then immunogenicity is reduced, but binding affinity is reduced
Solution Approach 1:
The patent applies local quality by making different parts of the antibody variable domain have different degrees of humanization. Specifically, CDR loops are fully humanized while framework regions retain some murine residues at key positions to maintain binding affinity. This selective humanization approach allows the antibody to have reduced immunogenicity in the CDR regions while preserving high affinity through strategic retention of murine residues in framework regions.
2Reliability
If more murine residues are retained in humanized antibodies, then binding affinity is improved, but immunogenicity increases
Solution Approach 1:
The patent applies parameter changes by systematically varying the degree and location of humanization across different antibody variants. Through phage library screening and mutagenesis, the patent optimizes the balance between murine and human residues at specific positions, creating a spectrum of humanization levels that can be selected based on the desired balance between affinity and immunogenicity.
3Manufacturing precision
If extensive mutagenesis and screening are performed to optimize antibodies, then binding specificity and affinity are improved, but manufacturing complexity and cost increase
Solution Approach 1:
The patent applies preliminary action by pre-selecting framework regions and CDR loops that have been optimized through prior mutagenesis and screening efforts. The humanized antibody variants are designed with predetermined sequences that have already been validated for binding specificity, reducing the need for extensive additional screening and simplifying the manufacturing process.
4Object-affected harmful factors
If CDR loops are fully humanized, then immunogenicity is reduced, but the physical stability of the antibody may be compromised
Solution Approach 1:
The patent applies local quality by differentiating the humanization strategy between CDR loops and framework regions. CDR loops are fully humanized to minimize immunogenicity, while framework regions retain strategic murine residues that contribute to structural stability. This localized approach allows each region to be optimized for its specific function: antigen binding and low immunogenicity for CDRs, and structural integrity for frameworks.
Data Source
AI summary
Provided herein are antibody molecules that bind specifically to C-MET and related nucleic acid molecules, vectors and host cells. Also provided herein are medical uses of such antibody molecules.