Dynamic Heavy Chain Antibody Libraries Using Flexible HVRs
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Solution Overview
Problem
Existing antibody libraries face limitations in diversity and screening efficiency, particularly in identifying antibodies with desired properties due to constraints on sequence variety and practical screening capabilities.
Innovation Solution
Development of dynamic antibody libraries containing flexible HVR sequences, allowing for high diversity and efficient identification of antibodies with high affinity and cross-reactivity, using synthetic polynucleotides encoding HVR-H1, HVR-H2, and HVR-H3 regions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If traditional antibody libraries are constructed from biological sources or synthesized, then sequence diversity is achieved, but library size is limited and screening becomes time-consuming and laborious
Solution Approach 1:
The patent applies parameter changes by systematically varying the HVR sequences according to defined formulas with specific amino acid constraints (e.g., X1 is F or Y, X2 is S or T, etc.). This allows generation of diverse antibody sequences with controlled variability, achieving high sequence diversity while maintaining manageable library sizes that can be efficiently screened.
Solution Approach 2:
The patent introduces dynamic units with flexible HVR sequences that can adopt multiple conformations. This dynamic approach allows the antibody libraries to explore a broader sequence space without proportionally increasing library size, thereby reducing screening time while maintaining diversity.
2Quantity of substance
If library size is increased to improve diversity, then more antibody variants are available, but screening efficiency decreases and becomes more exhaustive
Solution Approach 1:
By controlling the parameter space of HVR sequences through defined formulas with specific amino acid options at each position, the patent generates high diversity within a constrained framework. This allows creation of compact libraries that maintain broad diversity while remaining feasible for efficient screening.
Solution Approach 2:
The patent segments the antibody sequence into fixed framework regions and variable HVR regions. By applying formulas specifically to the HVR segments with controlled variability, diversity is concentrated where it matters most (binding specificity) while keeping the overall library size manageable for efficient screening.
3Adaptability or versatility
If HVR sequences are made flexible to recognize multiple epitopes, then binding versatility improves, but library complexity increases
Solution Approach 1:
The patent uses parameter changes by defining specific amino acid constraints in HVR formulas (e.g., X1 is F or Y, X3 is D, G, N, or S) that promote flexibility and conformational diversity. This enables antibodies to recognize multiple epitope types including conformational epitopes, while the constrained parameter space prevents exponential library complexity expansion.
Data Source
AI summary
Provided herein are libraries containing polynucleotides, where one of the polynucleotides encodes an antibody heavy chain with specific hypervariable regions HVR-H1 and HVR-H2. Further provided herein are libraries containing polynucleotides encoding a plurality of unique antibodies, wherein each antibody comprises a heavy chain variable region and a light chain variable region. Also provided are antibodies, polypeptide libraries, vector libraries, cells, non-human animals, antibody heavy chains, methods of making an antibody library, kits, and methods of generating a bispecific antibody related thereto.