Humanizing Antibody CDR Residues for Structural Fit
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing antibody modifications, such as CDR-grafted antibodies, often result in reduced antigen affinity and increased immunogenicity, limiting their utility as therapeutic agents due to foreignness to the human body.
Innovation Solution
Strategic modifications of non-human donor antibody amino acids in the CDR and adjacent FR residues to accommodate differences between donor and human acceptor antibodies, focusing on the CDR region to minimize immune response and maintain strong antigen binding.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If CDR-grafted antibodies are created using non-human donor CDRs in human framework regions, then the antibody becomes more human-like and less immunogenic, but the antigen binding affinity is reduced
Solution Approach 1:
The patent applies local quality by making specific amino acid substitutions only in the CDR regions where they are needed to maintain structural fit, rather than modifying the entire antibody. The framework regions remain fully human while localized modifications are made to CDR residues that contact the framework, thereby preserving overall human-like characteristics while fixing specific structural compatibility issues.
Solution Approach 2:
The patent changes amino acid parameters (specific residue identities) in the CDR regions to optimize the structural fit between CDR loops and human framework regions. By substituting specific non-human amino acids with human-compatible alternatives at critical positions, the patent maintains both antigen binding capability and reduced immunogenicity.
2Reliability
If framework region amino acids are changed from acceptor to donor sequences to improve affinity, then antigen binding affinity is improved, but immunogenicity increases
Solution Approach 1:
The patent segments the variable region into framework regions and CDR regions, and further segments the CDR regions into residues that contact the framework versus those that contact antigen. By making modifications only in the framework-contacting residues of CDRs and leaving the majority of framework regions unchanged, the patent achieves affinity improvement with minimal impact on immunogenicity.
Solution Approach 2:
The patent applies local quality by making specific amino acid substitutions only in the CDR regions where they are needed to maintain structural fit, rather than modifying the entire antibody. The framework regions remain fully human while localized modifications are made to CDR residues that contact the framework, thereby preserving overall human-like characteristics while fixing specific structural compatibility issues.
3Stability of the object's composition
If CDR residues are modified to accommodate human framework region differences, then structural fit and stability are improved, but the number of modifications required increases complexity
Solution Approach 1:
The patent applies partial action by identifying and modifying only the critical CDR residues that directly contact the framework regions, rather than modifying all CDR residues or all framework residues. This selective approach achieves sufficient structural fit improvement without requiring exhaustive modifications, thereby reducing complexity while maintaining stability.
Data Source
AI summary
The present invention is based, at least in part, on the discovery that strategic modifications of non-human donor antibody CDR residue(s) can be used to humanize antibodies. Such modifications modulate the 3D structural fit between donor antibody CDRs and human acceptor antibody framework regions that comprise the variable domains of a CDR-grafted antibody. Whereas prior art methods of humanization have relied on making framework substitutions (in which selected human framework residues are backmutated to the corresponding amino acid residue present in the non-human donor antibody), the instant invention is based, at least in part, on a method of humanizing antibodies in which selected CDR residues, and optionally adjacent FR residues, are changed in order to accommodate differences in FR amino acid sequences between donor and acceptor antibodies.