Antibody Library Design Using Germline VH-VL Pair Selection
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Solution Overview
Problem
Current methods for identifying therapeutic antibodies are inefficient due to high failure rates and long developmental timelines, with phage display libraries often producing antibodies that fail to meet rigorous criteria for market readiness, such as stability, expression levels, and safety.
Innovation Solution
A library of antibodies comprising germline gene sequences from the human immune repertoire, specifically variable heavy and light chain pairs that are frequently expressed and have favorable biophysical properties, such as stability and low immunogenicity, is created to enhance developability and safety.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If phage display libraries are used to identify therapeutic antibodies, then large numbers of antibodies can be tested for binding to targets, but most antibodies produced fail to meet rigorous criteria for stability, expression levels, and safety
Solution Approach 1:
The patent applies preliminary action by pre-selecting and incorporating only those variable heavy and light chain germline gene pairs that have been demonstrated to exhibit favorable biophysical properties (high stability, high expression levels, low immunogenicity) into the library design before screening begins. This upfront curation ensures that all antibodies produced from the library have a high probability of meeting developability criteria, eliminating the need to screen through large numbers of poorly performing antibodies.
Solution Approach 2:
The patent changes the parameters of the antibody library by restricting it to specific germline gene pairs with known optimal biophysical characteristics. Instead of using diverse or synthetic libraries with uncertain properties, the invention defines the library using only germline pairs that have been characterized to have high thermal stability, high expression yields, and low immunogenicity, thereby fundamentally changing the quality parameters of the antibodies produced.
2Adaptability or versatility
If diverse antibody libraries are created to cover any therapeutic target, then broad applicability is achieved, but the risk of including antibodies with poor stability and expression properties increases
Solution Approach 1:
The patent changes the parameters by defining the library using only germline gene pairs with proven optimal biophysical properties. This parameter restriction maintains versatility for targeting any therapeutic antigen while ensuring all antibodies have high thermal stability and serum stability, as these stability properties are inherent to the selected germline pairs regardless of the target antigen.
Solution Approach 2:
The patent applies preliminary action by pre-characterizing and selecting only those germline gene pairs that exhibit high thermal stability and serum stability before constructing the library. This upfront selection based on stability data ensures that all subsequent antibodies will inherit these favorable stability properties, eliminating the need to screen for stability after library construction.
3Adaptability or versatility
If libraries include all possible variable heavy and light chain combinations, then comprehensive coverage is achieved, but the time and cost of screening increases significantly
Solution Approach 1:
The patent applies the taking out principle by extracting and excluding from the library all variable heavy and light chain germline gene pairs that do not exhibit favorable biophysical properties. Instead of including all possible combinations, the invention selectively extracts only the beneficial germline pairs with high stability and expression characteristics, thereby dramatically reducing library size and screening requirements while maintaining therapeutic effectiveness.
Solution Approach 2:
The patent changes the parameters by defining the library using only germline gene pairs with proven optimal biophysical properties. This parameter restriction maintains versatility for targeting any therapeutic antigen while ensuring all antibodies have high thermal stability and serum stability, as these stability properties are inherent to the selected germline pairs regardless of the target antigen.
4Ease of operation
If antibodies are selected without considering germline gene origins, then screening flexibility is maintained, but immunogenicity risk increases
Solution Approach 1:
The patent changes the parameters by defining the library using only germline gene pairs with proven optimal biophysical properties. This parameter restriction maintains versatility for targeting any therapeutic antigen while ensuring all antibodies have high thermal stability and serum stability, as these stability properties are inherent to the selected germline pairs regardless of the target antigen.
Data Source
AI summary
The present disclosure enables methods of identifying the VH and VL class pairs in the human immune repertoire, determining the VH and VL class pairs that are most prevalent and those having favorable biophysical properties. More specifically, the collections of the present disclosure comprise the most prevalent and/or preferred VH and VL class pairings with highly diversified CDRs.