Germline Antibody Library for Developability Screening
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Solution Overview
Problem
Current methods for identifying therapeutic antibodies are inefficient due to high failure rates and long developmental timelines, resulting in high costs and limited availability of effective medicines, as they often fail to meet rigorous criteria for stability, expression, and safety.
Innovation Solution
A collection of antibodies comprising germline protein sequences from the human immune repertoire, specifically variable heavy and light chain pairs with favorable biophysical properties, is created to enhance developability and safety, using in silico analysis and testing to select pairs that meet criteria for stability, expression, and low immunogenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If traditional phage display technology is used to identify therapeutic antibodies, then large libraries can be screened, but the identification process takes over fifteen years and has high failure rates
Solution Approach 1:
The patent applies preliminary action by pre-selecting and characterizing antibody sequences from the human immune repertoire before they are used for therapeutic development. The sequences are evaluated for developability properties (stability, expression, solubility, low aggregation propensity) in advance, so that only pre-validated sequences are advanced to clinical development, thereby reducing both time and failure rates
Solution Approach 2:
The patent changes the selection parameters from traditional affinity-only screening to multi-parameter evaluation including developability properties. By introducing new selection criteria such as thermal stability, expression levels, and aggregation propensity alongside affinity, the patent identifies antibodies that meet both binding and development requirements, improving success rates while maintaining screening efficiency
2Reliability
If rigorous development criteria are applied to ensure stability and safety, then therapeutic quality is improved, but identification time and cost increase
Solution Approach 1:
The patent performs preliminary characterization of developability properties during the initial library construction phase rather than during later development stages. By assessing stability, expression, and aggregation properties upfront, the patent eliminates time-consuming optimization steps later in development while ensuring rigorous quality standards are met
Solution Approach 2:
The patent uses naturally occurring human immune repertoire sequences that inherently possess favorable developability properties. By selecting from sequences that have evolved through natural selection, the patent obtains antibodies with intrinsic stability and low immunogenicity, reducing the need for extensive engineering and validation time
3Reliability
If diverse antibody libraries are screened to ensure safety and efficacy, then treatment effectiveness is improved, but development cost exceeds one billion dollars
Solution Approach 1:
The patent applies local quality by focusing diversity efforts on the complementarity-determining regions (CDRs) while keeping the framework regions constrained to human-like sequences. This allows the antibody to maintain high affinity and specificity through diverse CDRs while ensuring developability and low immunogenicity through humanized frameworks, reducing development costs by eliminating the need to screen diverse entire sequences
Data Source
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AI summary
The present disclosure enables collections of variable heavy chain and variable light chain pairs comprising, in part, germline protein sequences that are pre-selected for functional properties relevant to developability, wherein the collections may be used to select against any antigen using, for example, phage display.