Antibody Libraries with Natural CDRs and Liability Screening
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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, unpaired cysteines, and aggregation motifs, to enhance antibody developability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If synthetic antibody libraries are constructed with randomized CDR sequences into framework scaffolds, then genetic diversity and expression are improved, but many non-functional members are included and natural diversity is excluded
Solution Approach 1:
The patent applies preliminary action by pre-selecting framework scaffolds based on their expression characteristics and stability properties before constructing the library. This ensures that only well-behaved frameworks are used, improving the functional proportion of members while maintaining genetic diversity through subsequent CDR randomization.
Solution Approach 2:
The patent changes parameters by optimizing framework scaffold selection criteria to prioritize expression levels and stability. By adjusting these selection parameters, the library achieves a better balance between genetic diversity and functional proportion, reducing non-functional members while preserving natural diversity characteristics.
2Reliability
If natural antibody libraries are constructed from B-cells, then biological functionality is improved, but obtaining large numbers of B-cells is challenging and expression properties are poor
Solution Approach 1:
The patent applies segmentation by separating the library construction into two independent parts: selecting high-quality framework scaffolds from natural antibodies and independently randomizing CDR regions. This allows obtaining sufficient B-cells for framework selection while achieving high diversity through synthetic CDR combinations, thus resolving the productivity limitation.
Solution Approach 2:
The patent transitions from a single-dimension approach (either natural or synthetic) to a hybrid approach combining natural frameworks with synthetic CDR diversity. This dimensional change allows the library to achieve both high biological functionality from natural frameworks and high productivity through extensive CDR randomization.
3Quantity of substance
If CDRs are randomly introduced into frameworks, then diversity is increased, but non-functional members and aggregation liabilities are included
Solution Approach 1:
The patent applies preliminary action by pre-screening and selecting framework scaffolds with favorable stability and expression properties before CDR introduction. This preliminary selection reduces aggregation liabilities at the framework level, allowing subsequent CDR randomization to achieve diversity without proportionally increasing harmful aggregation factors.
4Adaptability or versatility
If antibodies are selected from vast libraries, then specific properties can be directly selected, but non-functional members reduce the effective diversity
Solution Approach 1:
The patent applies preliminary action by pre-selecting framework scaffolds with optimized expression and stability characteristics before constructing the final library. This ensures that a high proportion of members are functional, thereby increasing effective diversity while maintaining the capability to select for specific properties from the diverse pool.
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.