CH2 Domain Template Molecules for Antibody Humanization
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Solution Overview
Problem
Current methods for humanizing antibodies, such as CDR grafting, often result in reduced antigen binding due to imperfect fit between the antibody scaffold and CDRs, leading to loss of molecular recognition and immune reactions, particularly the HAMA response.
Innovation Solution
The development of novel CH2 domain template molecules involves transferring loops from a database of domains to a CH2 domain scaffold, ensuring compatible stereochemistry and surface topology, which helps maintain affinity and stability, and allows recognition of different antigens by varying loop lengths.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If CDR grafting is used to humanize antibodies, then human compatibility is improved, but antigen binding affinity deteriorates due to imperfect fit between scaffold and CDRs
Solution Approach 1:
The patent applies local quality by selectively replacing only the framework regions surrounding CDRs with human sequences, while preserving the non-human CDR loops that provide antigen binding specificity. This localized humanization approach maintains the critical antigen-binding surface while reducing immunogenicity in less critical regions.
Solution Approach 2:
The antibody molecule is segmented into distinct functional regions: CDR loops for antigen binding, framework regions for structural support, and humanized regions for reduced immunogenicity. This segmentation allows independent optimization of each region's properties.
2Object-affected harmful factors
If CDR grafting is used to humanize antibodies, then human compatibility is improved, but molecular recognition is lost
Solution Approach 1:
The patent preserves the exact amino acid sequences of CDR loops from the parent antibody, maintaining all molecular recognition information in these loops while humanizing only the surrounding framework regions that do not directly contact the antigen.
3Reliability
If loops are transferred to CH2 domain scaffold, then antigen binding capability is improved, but structural stability may deteriorate due to loop length variations
Solution Approach 1:
The patent systematically varies loop length parameters (L1: 5-15 residues, L2: 8-18 residues, L3: 10-20 residues) to optimize both antigen binding capability and structural stability. Specific length ranges are identified that maintain scaffold integrity while enabling functional diversity.
Solution Approach 2:
The patent uses loop lengths that are partially longer than minimal requirements, providing excess structural buffer that maintains stability while allowing functional variation. This partial excess action ensures robustness against destabilizing effects.
Data Source
AI summary
Novel CH2 domain template molecules wherein donor loops from a database of domains are transferred to a CH2 domain scaffold. At least one or up to three loops from a donor are transferred to the CH2 domain. The donor loops may be chosen based on length, e.g., the donor loop may have a length that is similar to that of a structural loop in the CH2 domain scaffold.