Antibody Affinity Improvement via Framework Region Residue Modification
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Solution Overview
Problem
Current methods for improving antibody affinity for antigens often require modifying amino acid sequences in complementarity determining regions (CDR), which can disrupt antigen specificity, and there is a need for a method that enhances affinity without altering the CDR sequence.
Innovation Solution
Modifying specific amino acid residues in the framework regions (FR) of antibodies, specifically changing the 17th, 18th, and 20th positions of the light chain to charged residues, while maintaining the CDR sequence, to improve antigen binding affinity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If amino acid residues in complementarity determining regions (CDR) are modified to improve antibody affinity, then binding affinity improves, but antigen specificity is disrupted
Solution Approach 1:
The invention divides the antibody variable region into two functional segments: CDR regions that maintain antigen specificity and framework regions (FR) that control binding affinity. By segmenting the modification targets to exclusively use FR residues (specifically positions 17, 18, and 20 of the light chain), the patent allows affinity optimization without compromising CDR-mediated specificity.
Solution Approach 2:
The patent applies local quality by making specific modifications only at predetermined framework region positions (17th, 18th, and 20th amino acid residues of the light chain) while leaving the rest of the antibody sequence unchanged. This localized modification approach ensures that only the binding interface properties are altered without affecting the antigen recognition properties maintained by the CDR regions.
2Reliability
If multiple amino acid residues are changed to charged residues, then antibody affinity improves, but structural stability may be compromised
Solution Approach 1:
The patent performs preliminary action by pre-identifying and selecting specific framework region positions (17, 18, and 20 of the light chain) that are most likely to influence binding affinity based on their solvent accessibility and distance from the antigen-binding interface. This predetermined selection approach allows systematic introduction of charged residues at optimal positions without random structural disruption.
Solution Approach 2:
The patent applies parameter changes by systematically varying the charge state of amino acid residues at predetermined framework positions. By changing residues to charged forms (such as introducing positive charges via lysine or arginine), the patent optimizes electrostatic interactions with the antigen while maintaining overall structural integrity through controlled, position-specific modifications.
Data Source
AI summary
Disclosed is a method for improving affinity of an antibody for an antigen, comprising, in an unmodified antibody, improving affinity for an antigen as compared to the unmodified antibody, by changing 17th, 18th and 20th amino acid residues of a light chain defined by Kabat method to charged amino acid residues.