Humanized VHH Antibody Scaffold Reducing Immunogenicity
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Solution Overview
Problem
Current single domain antibody libraries derived from non-human sources face challenges with immunogenicity and limited therapeutic application due to their non-human origin, despite having advantages like high solubility and specificity, as they can trigger a human immune response when administered.
Innovation Solution
A fully humanized, recombinant single domain antibody library is developed by replacing camelid-specific amino acids in the VHH framework with human counterparts, maintaining the scaffold's stability and specificity while reducing immunogenicity, allowing for high-affinity binding in the nano/pico-molar range and intracellular activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If camelid single domain antibodies are used, then high solubility and specificity are achieved, but immunogenicity increases due to non-human origin
Solution Approach 1:
The patent applies parameter changes by systematically substituting camelid-specific amino acid residues in the framework regions with human counterparts. Specifically, residues at positions 42, 45, 49, and 52 in the framework region are changed from camelid to human amino acids, transforming the molecular parameters of the antibody scaffold to reduce immunogenicity while preserving functional properties
Solution Approach 2:
The invention creates a humanized copy of the camelid single domain antibody framework. Instead of using the original camelid sequence, a humanized version is constructed by copying the overall structural framework and selectively replacing specific residues with human amino acids, thereby creating a derivative that mimics human antibodies and reduces immune recognition
2Adaptability or versatility
If humanization is performed to reduce immunogenicity, then therapeutic applicability improves, but binding affinity and stability may be reduced
Solution Approach 1:
The patent applies local quality by making targeted, localized changes only at specific framework positions (42, 45, 49, 52) rather than throughout the entire antibody structure. The CDR regions and most of the framework remain unchanged, preserving local binding properties while only modifying specific local residues to reduce immunogenicity
Solution Approach 2:
The invention uses partial action by performing limited humanization at only four specific framework positions rather than comprehensive humanization of the entire sequence. This partial approach is sufficient to reduce immunogenicity while minimizing disruption to binding affinity and structural stability
Data Source
AI summary
The present invention relates to the identification of a fully humanized single domain antibody scaffold as well as its use in generating synthetic single domain antibodies. The invention further relates to antigen-binding proteins comprising said single domain antibody scaffold and their use in therapy.