Antibody Libraries: CDR Diversification for Functional Developability
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Solution Overview
Problem
Current antibody libraries face challenges in achieving high genetic diversity while ensuring functional and well-expressed antibodies, as they often include non-functional members and lack natural diversity screening.
Innovation Solution
Development of antibody libraries comprising diversified heavy and light chain variable domains with complementary determining regions (CDRs) derived from naturally-occurring antibodies, excluding liabilities such as glycosylation sites and aggregation motifs, to enhance antibody developability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If synthetic antibody libraries are constructed with randomized CDR sequences, then genetic diversity is increased, but the proportion of non-functional members increases
Solution Approach 1:
The patent applies preliminary action by pre-selecting framework regions from naturally occurring antibodies that have already undergone quality control in B cells. This preliminary selection ensures that the framework regions are biologically functional before CDR randomization, thereby increasing the proportion of functional members in the synthetic library while maintaining genetic diversity.
Solution Approach 2:
The patent applies local quality by differentiating between framework regions and CDR regions. The framework regions are selected from natural antibodies to ensure biological functionality, while the CDR regions are randomized to provide genetic diversity. This localized application of different selection strategies optimizes both functional proportion and diversity.
2Reliability
If natural antibody libraries are used, then functional proportion is increased, but genetic diversity is limited
Solution Approach 1:
The patent applies segmentation by dividing the antibody structure into framework regions and CDR regions. Framework regions are sourced from natural antibodies to ensure functionality, while CDR regions are randomized to expand diversity. This segmentation allows the library to simultaneously achieve high functional proportion and genetic diversity.
Solution Approach 2:
The patent merges the advantages of natural antibody libraries (high functional proportion) with the advantages of synthetic libraries (high genetic diversity). By combining naturally sourced framework regions with randomized CDRs, the patent creates a hybrid library that achieves both high functionality and extensive diversity.
3Adaptability or versatility
If CDRs are randomized in synthetic libraries, then diversity is improved, but expression quality deteriorates
Solution Approach 1:
The patent applies preliminary action by pre-selecting framework regions from natural antibodies that have proven expression quality. This preliminary selection ensures that the framework regions are optimized for expression before CDR randomization, thereby maintaining expression quality while achieving diversity through CDR variation.
4Reliability
If natural antibodies are used directly, then functional quality is improved, but recombinant expression performance deteriorates
Solution Approach 1:
The patent applies segmentation by separating framework regions (selected for functional quality from natural antibodies) from CDR regions (optimized for expression). This segmentation allows the framework to provide functional quality while the CDRs contribute to expression performance in recombinant systems.
Data Source
AI summary
Antibody libraries comprising a plurality of heavy chain variable domains and/or a plurality of light chain variable domains, which comprise complementary determining regions (CDRs) found in naturally-occurring human antibodies, and methods of making such antibody libraries. The antibody libraries are free of members that comprise one or more liabilities affecting one or more features of such members. Further, the antibody libraries comprise members having heavy chain and/or light chain CDRs not found in the same naturally-occurring human antibody.