Synthetic Antibody Library via Codon Replacement for Low Immunogenicity
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Solution Overview
Problem
Current methods for generating antibody libraries face limitations such as immunogenicity issues with chimeric and nonhuman monoclonal antibodies, challenges in controlling epitope formation, and difficulties in generating antibodies to self-antigens due to high sequence homology between humans and mice, leading to reduced efficacy and safety concerns.
Innovation Solution
A synthetic antibody library is created using codon replacement technology to design and express antibodies with modified CDRs of varying lengths and amino acid frequencies, allowing for optimized chain lengths and frequencies to enhance antigen binding specificity and affinity, and cloned into phage or yeast display systems for screening.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If chimeric or nonhuman monoclonal antibodies are used, then antibody diversity is achieved, but immunogenicity increases leading to reduced efficacy and safety
Solution Approach 1:
The patent applies parameter changes by systematically varying CDR length (4-23 amino acids) and amino acid frequency at specific positions to generate diverse human antibody sequences that maintain low immunogenicity while achieving the desired diversity for therapeutic applications
Solution Approach 2:
The patent applies local quality by introducing controlled variability specifically in the CDR regions (complementarity determining regions) of the antibody variable domains, while keeping the framework regions consistent with human antibody sequences, thereby achieving diversity where needed without triggering immune responses
2Productivity
If traditional immunization or hybridoma technology is used, then antibodies are generated, but control over epitope formation is lost and safety issues arise
Solution Approach 1:
The patent applies preliminary action by pre-designing the CDR sequences with specific length and amino acid frequency parameters before library construction, allowing control over epitope formation characteristics in advance rather than relying on random immunization outcomes
Solution Approach 2:
The patent applies segmentation by dividing the antibody variable domain into framework regions and CDR regions, with further segmentation of CDRs into individual amino acid positions, allowing independent optimization of each segment's properties for controlled epitope formation
3Productivity
If murine hybridoma technology is used for antibody generation, then antibodies are produced, but generation of antibodies to self-antigens is challenging due to high sequence homology between humans and mice
Solution Approach 1:
The patent applies inversion by reversing the traditional approach: instead of using murine antibodies and attempting to humanize them, the patent directly generates human antibody sequences with controlled CDR diversity, thereby eliminating the self-antigen recognition problem from the outset
Data Source
AI summary
The present disclosure relates to a method of generating an antibody library, not limiting to a synthetic antibody gene expression library built on pool of consensus nucleic acid sequences by using codon replacement technology. The present disclosure also relates to a synthetic antibody library generated by employing the method of the present disclosure and application(s) of said antibody library.