Human-Framework Immunoglobulin Scaffolds With Non-Human CDR3
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Solution Overview
Problem
Existing monoclonal antibodies produced from rodent hosts are immunogenic in humans, leading to undesirable immune responses and limited binding affinity when humanized using traditional methods.
Innovation Solution
A method for producing a population of nucleic acids encoding immunoglobulin variable domains with non-human CDR3 amino acid sequences embedded in human framework sequences, allowing for rapid humanization and identification of target-binding antibodies without cloning into different vectors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If traditional humanization methods are used to reduce immunogenicity, then human compatibility is improved, but binding affinity decreases significantly
Solution Approach 1:
The antibody variable region is segmented into distinct functional domains: CDR1 and CDR2 are humanized to reduce immunogenicity, while CDR3 is retained as non-human to preserve binding affinity. This segmentation allows different parts of the antibody to have different species origins, resolving the contradiction between human compatibility and binding affinity.
Solution Approach 2:
Different regions of the antibody variable domain are assigned different species characteristics locally. The CDR1 and CDR2 regions use human sequences for low immunogenicity, while the CDR3 region uses non-human sequences for high binding affinity. This local differentiation allows each region to optimize its function without compromising the other.
2Manufacturing precision
If multiple human templates are evaluated for humanization, then selection of optimal template is improved, but time required for humanization increases
Solution Approach 1:
The method performs preliminary computational evaluation of multiple human templates against the non-human antibody CDR sequences before actual humanization. By pre-ranking templates based on homology and functional compatibility, the process identifies the optimal template in advance, reducing the time needed for iterative selection and experimentation.
Solution Approach 2:
The method creates a computational model or copy of the humanization process that evaluates multiple templates simultaneously through in silico analysis. This virtual copying allows rapid assessment of template suitability without requiring physical experimentation for each template, significantly reducing humanization time while maintaining selection accuracy.
3Ease of manufacture
If conventional humanization approaches are used, then antibody production is simplified, but multiple selection rounds and vector cloning are required
Solution Approach 1:
The method merges the humanization process with the selection process into a single integrated step. By combining computational template evaluation with functional screening in one workflow, the method eliminates the need for separate selection rounds and multiple vector cloning steps, reducing overall process complexity while maintaining ease of manufacture.
Data Source
AI summary
The present invention relates to a method for producing a population of nucleic acids encoding at least one protein comprising at least one immunoglobulin variable domain having a non-human-derived CDR3 amino acid sequence embedded in essentially human framework sequences, as well as to a population of nucleic acids and a population of proteins relates thereto and uses thereof.