PD1 Binding Antibody Humanization via Local Quality
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Solution Overview
Problem
Current antibody therapeutics targeting PD1 for cancer treatment face challenges due to inefficiencies in humanization processes, leading to reduced binding affinity and increased immunogenicity, with existing methods failing to accurately predict residue modifications that maintain antigen binding while minimizing clinical risks.
Innovation Solution
Development of anti-PD1 antibodies with specific heavy and light chain variable region sequences that enhance binding specificity and affinity to human and cynomolgus monkey PD1, while reducing off-target binding and immunogenicity, through a process involving CDR grafting and mutagenesis to achieve optimal humanization and stability.
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 have different properties: the CDR loops retain non-human sequences to maintain high binding affinity to PD1, while the framework regions are humanized to reduce immunogenicity. This selective humanization approach allows each region to optimize its function locally.
Solution Approach 2:
Instead of the conventional approach of humanizing CDRs and back-mutating frameworks, this patent inverts the strategy by humanizing only the framework regions while keeping CDRs in their original non-human form. This reversal maintains binding affinity while achieving humanization benefits.
2Reliability
If more murine residues are introduced to restore binding affinity, then binding affinity is improved, but immunogenicity increases
Solution Approach 1:
The patent applies local quality by making different parts of the antibody have different properties: the CDR loops retain non-human sequences to maintain high binding affinity to PD1, while the framework regions are humanized to reduce immunogenicity. This selective humanization approach allows each region to optimize its function locally.
3Adaptability or versatility
If basic CDR grafting is used, then humanization is achieved, but physical stability and immunogenicity risks remain
Solution Approach 1:
The patent applies parameter changes by systematically evaluating and selecting specific framework residue substitutions that optimize both humanization and physical stability. The method involves testing multiple framework variants to identify those with improved stability characteristics while maintaining humanized status.
4Measurement precision
If animal testing is used to assess immunogenicity, then preclinical data is obtained, but predictive accuracy for human immune response is low
Solution Approach 1:
The patent replaces animal-based immunogenicity testing with in silico computational methods that predict human T-cell epitopes. This substitution uses bioinformatics algorithms to identify potential immunogenic regions based on human immune system characteristics, providing more accurate predictions for human clinical responses.
Data Source
AI summary
Provided herein are antibody molecules that bind specifically to Programmed cell death 1 (PD1) and related nucleic acid molecules, vectors and host cells. Also provided herein are medical uses of such antibody molecules.