IL-13 Antibody CDR Engineering for Cross-Species Binding
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Solution Overview
Problem
There is a need for antibodies that bind to both human and cynomolgus monkey IL-13 with high affinity to facilitate toxicological studies, as existing antibodies like AMGN12 show a significant affinity gap between the two species, with AMGN12 displaying strong binding to human IL-13 but weak binding to cynomolgus monkey IL-13.
Innovation Solution
Development of antigen binding proteins with specific amino acid sequence changes in the CDRs of Ab731 to increase binding affinity to cynomolgus monkey IL-13, while maintaining binding affinity to human IL-13, achieved through the HuTARG platform and XenoMouse technology, resulting in antibodies with over 100-fold affinity improvement and 10-fold potency improvement in biological assays.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibody AMGN12 is used to bind human IL-13 with high affinity, then binding affinity to human IL-13 is improved, but binding affinity to cynomolgus monkey IL-13 deteriorates
Solution Approach 1:
The patent applies local quality by introducing specific amino acid substitutions at particular positions (e.g., HCDR3 region residues 100, 102, 104) within the antibody variable domain. These localized changes at specific binding interface positions enhance cynomolgus monkey IL-13 binding while preserving human IL-13 binding affinity, demonstrating that targeted local modifications can differentially affect binding to different species targets.
Solution Approach 2:
The patent employs parameter changes by systematically varying amino acid sequences at defined positions in the antibody variable domain (particularly HCDR3). By changing the chemical parameters (amino acid type, charge, hydrophobicity) at these positions, the antibody's binding characteristics are tuned to achieve high affinity for both human and cynomolgus monkey IL-13, transforming the binding parameters through controlled sequence modifications.
2Measurement precision
If antibody sequence is optimized for human IL-13 binding, then binding specificity to human IL-13 is improved, but cross-species binding capability deteriorates
Solution Approach 1:
The patent achieves universality by designing antibody variable domains that can bind multiple species variants of IL-13 (both human and cynomolgus monkey). Through specific amino acid substitutions in the HCDR3 region, the antibody gains the ability to recognize conserved epitopes across species while maintaining high affinity, making it universally applicable for both human therapeutic use and cynomolgus monkey toxicological studies.
Solution Approach 2:
The patent applies local quality by introducing specific amino acid substitutions at particular positions (e.g., HCDR3 region residues 100, 102, 104) within the antibody variable domain. These localized changes at specific binding interface positions enhance cynomolgus monkey IL-13 binding while preserving human IL-13 binding affinity, demonstrating that targeted local modifications can differentially affect binding to different species targets.
3Loss of time
If conventional antibody development methods are used, then development time is reduced, but affinity gap between species cannot be closed
Solution Approach 1:
The patent applies preliminary action by pre-defining the target amino acid substitution patterns in the antibody variable domain before full-scale antibody development. By establishing the framework of necessary mutations (particularly in HCDR3) upfront, the development process is streamlined to focus on optimizing these predetermined positions, thereby closing the affinity gap efficiently without extensive trial-and-error experimentation.
Solution Approach 2:
The patent employs parameter changes by systematically varying amino acid sequences at defined positions in the antibody variable domain (particularly HCDR3). By changing the chemical parameters (amino acid type, charge, hydrophobicity) at these positions, the antibody's binding characteristics are tuned to achieve high affinity for both human and cynomolgus monkey IL-13, transforming the binding parameters through controlled sequence modifications.
Data Source
AI summary
The present invention is related to antibodies directed to IL-13 and uses of such antibodies. For example, in accordance with the present invention, there are provided human monoclonal antibodies directed to IL-13. Isolated polynucleotide sequences encoding, and amino acid sequences comprising, heavy and light chain immunoglobulin molecules, particularly sequences corresponding to contiguous heavy and light chain sequences spanning the framework regions (FR's) and/or complementarity determining regions (CDR's), are provided. Additionally, methods of using these antibodies to treat patients are also provided.