HC-CDR3 Antibody Library Reducing Combinatorial Redundancy
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Solution Overview
Problem
Recombinant antibody libraries face challenges in effectively representing and selecting therapeutic antibody candidates due to over-representation of short HC-CDR3 loops and under-representation of longer loops, leading to redundancy and reduced coverage of mid-range loop lengths, which complicates the identification of suitable therapeutic antibodies.
Innovation Solution
A library design that optimizes HC-CDR3 loop length distribution and amino acid diversity, reducing redundancy and enhancing coverage by restricting diversity to the HC-CDR3 region and the position preceding it, allowing for a balanced representation of HC-CDR3 loop lengths, particularly well-representing those frequently observed in therapeutic antibodies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If diversity is introduced in multiple CDR regions in a completely random fashion, then the overall diversity of the library increases, but combinatorial redundancy increases for short HC-CDR3 loops and coverage of longer loop lengths decreases
Solution Approach 1:
The patent extracts diversity introduction from multiple CDR regions and concentrates it solely in the HC-CDR3 region. This eliminates the combinatorial redundancy problem by removing the random combination of variants from other CDR regions, while maintaining effective diversity through focused variation in HC-CDR3 loop length and sequence.
Solution Approach 2:
The patent applies local quality by making the HC-CDR3 region the sole focus of diversity introduction, with specific attention to loop length variation. Other CDR regions are kept constant or minimized, creating a localized diversity strategy that avoids the pitfalls of global random combination while effectively exploring the HC-CDR3 sequence space.
2Reliability
If HC-CDR3 loop length distribution follows the natural bell-shaped distribution with maximum at length 12, then the library represents natural antibodies well, but therapeutic antibody candidates with shorter loops (length 10) are under-represented
Solution Approach 1:
The patent changes the loop length distribution parameter from the natural bell-shaped distribution to a modified distribution that over-represents shorter loops (particularly length 10). This parameter change aligns the library with therapeutic antibody characteristics while maintaining reasonable coverage of other lengths, thereby improving adaptability for therapeutic candidate selection.
3Adaptability or versatility
If each HC-CDR3 variant is combined with random variants from other CDR regions, then combinatorial diversity is maximized, but the same HC-CDR3 variant is explored with limited combinations due to redundancy
Solution Approach 1:
The patent extracts the source of combinatorial redundancy by removing random variation from other CDR regions. This eliminates the waste of exploring the same HC-CDR3 variant with redundant combinations, while preserving effective diversity through focused variation in HC-CDR3 itself. The result is improved exploration efficiency without sacrificing adaptability.
Data Source
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AI summary
The present invention provides for a library of vectors comprising human HC-CDR3 regions of varying length, wherein the diversity of said library is focused on the HC-CDR3 region only and diversity has been optimized such that redundancy is reduced for short HC-CDR3 loops and coverage of HC-CDR3 region variants for longer loop lengths has been increased. The library of the present invention is displayed on phage for selection against target antigens.