Universal Antibody Library Design for Therapeutic Screening
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Solution Overview
Problem
Current methods for identifying desirable antibodies are limited by the lack of comprehensive representation of antibody sequences, leading to immunogenic issues and inefficiencies in screening and affinity maturation, particularly in therapeutic applications.
Innovation Solution
A universal antibody library (UAL) is created using walk-through mutagenesis (WTM) or look-through mutagenesis (LTM) to systematically represent all desirable candidate antibodies, ensuring non-immunogenicity and optimized diversity, allowing for efficient screening and affinity maturation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If human libraries are used to identify antibodies, then the antibodies are derived from human sequences, but the libraries lack comprehensive representation of valuable antibody sequences and require considerable redesign or humanization for therapeutic applications
Solution Approach 1:
The antibody variable region is segmented into framework regions (FR1-FR4) and complementarity determining regions (CDR1-CDR3). The patent systematically varies only the CDR regions while keeping frameworks constant, allowing comprehensive exploration of antibody diversity in a manageable, organized manner that resolves the contradiction between sequence diversity and therapeutic applicability.
Solution Approach 2:
The patent creates a universal antibody library framework that can represent all desirable candidate antibodies against any antigen class. By establishing a standardized variable region structure with systematic CDR variation, the library achieves universal applicability for identifying therapeutic antibodies while maintaining comprehensive sequence diversity representation.
2Quantity of substance
If synthetic or consensus libraries are used to be comprehensive, then they encode diverse sequences, but they contain non-naturally occurring sequences that are immunogenic and are difficult to screen
Solution Approach 1:
The patent applies local quality by introducing diversity only in the CDR regions (the local binding sites) while maintaining the natural human framework regions unchanged. This ensures that the diverse sequences are confined to functional regions, preserving natural immunological compatibility in the framework while achieving comprehensive diversity where needed for antigen recognition.
Solution Approach 2:
The patent performs preliminary action by pre-selecting and validating framework regions from natural human antibodies before constructing the library. This preliminary selection ensures that only naturally occurring, non-immunogenic frameworks are used as bases, preventing immunogenicity issues before they arise in the final antibody candidates.
3Quantity of substance
If synthetic libraries contain too much diversity to be comprehensive, then they represent all possible sequences, but they are difficult to screen and require exceedingly large libraries for meaningful exploration
Solution Approach 1:
By segmenting the antibody variable region into fixed frameworks and variable CDRs, the patent reduces the combinatorial complexity from varying entire antibody sequences to systematically combining a limited set of frameworks with a controlled set of CDR variations. This segmentation makes the library size manageable while preserving comprehensive diversity in the antigen-binding regions.
Solution Approach 2:
The patent applies parameter changes by controlling the degree of diversity introduction in the CDR regions rather than creating completely random or exhaustive sequences. By adjusting the number and type of variations in CDR positions, the library achieves meaningful diversity exploration at a scale that can be practically screened, optimizing the balance between comprehensiveness and screening feasibility.
Data Source
AI summary
Universal antibody libraries are described which are synthetic and derived from expressed human antibody sequences selected accordingly to certain criteria, for example, that the sequences are derived from naturally-occurring antibodies expressed in response to a certain antigen class (e.g., small molecule, polysaccharide, peptide, or protein) and having CDR regions engineered for optimal diversity. Methods for making and screening such libraries for isolating therapeutics suitable for treating disease are also disclosed.