Anti-CD52 Antibody Stability via Light Chain CDR1 Mutations
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Solution Overview
Problem
Anti-CD52 antibodies experience reduced binding affinity over time and under certain pH and temperature conditions, leading to instability and decreased effectiveness in storage and therapeutic applications.
Innovation Solution
Engineering variant antibodies with specific single amino acid substitutions at position 11 of the light chain CDR1, such as Ab21, Ab16, and Ab20, which retain or surpass the binding affinity and stability of the parent antibody Ab26, while maintaining or improving biological potency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If anti-CD52 antibodies are stored over time or exposed to high pH and temperature conditions, then their binding affinity decreases, but their stability should be improved
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence at specific positions (particularly position 11 of light chain CDR1) to alter the antibody's physical and chemical properties. This structural parameter change enables the antibody to maintain binding affinity under varying storage conditions including time, pH, and temperature exposure.
Solution Approach 2:
The patent converts the harmful effect of environmental conditions (time, pH changes, temperature) that normally degrade antibody binding affinity into a beneficial selection criterion. By screening variants under these stressful conditions, the patent identifies mutants that not only resist degradation but actually demonstrate improved stability, turning the harmful environmental factors into a tool for selecting superior antibody variants.
2Stability of the object's composition
If single amino acid substitutions are introduced at position 11 of light chain CDR1, then stability is improved, but binding affinity may be compromised
Solution Approach 1:
The patent systematically changes the amino acid parameter at position 11 of light chain CDR1, testing multiple substitutions (Serine, Alanine, Valine, Leucine, Isoleucine, Threonine, Methionine, Phenylalanine, Tyrosine, Tryptophan, Lysine, Arginine, Histidine, Asparagine, Glutamine, Aspartic acid, Glutamic acid, Cysteine). This parameter exploration identifies specific substitutions that simultaneously improve stability and preserve or enhance binding affinity.
Solution Approach 2:
The patent applies local quality by making a targeted amino acid substitution at a specific local position (position 11 of light chain CDR1) rather than globally modifying the entire antibody structure. This localized change allows precise control over stability properties while minimizing disruption to the overall binding interface and maintaining antigen recognition capabilities.
3Duration of action of stationary object
If variant antibodies are developed to improve stability, then consistency over time is enhanced, but device complexity increases
Solution Approach 1:
The patent employs parameter changes through site-directed mutagenesis at a single defined position (position 11 of light chain CDR1), which is a relatively simple and well-established molecular biology technique. This focused approach to parameter modification achieves improved temporal consistency without requiring complex multi-site engineering or sophisticated structural redesign.
Solution Approach 2:
The patent applies partial action by introducing only a single amino acid substitution at a specific position rather than making multiple changes throughout the antibody structure. This minimal intervention strategy achieves the desired stability improvement with reduced engineering complexity compared to comprehensive antibody redesign approaches.
Data Source
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AI summary
Anti-human CD52 antibodies and antigen-binding fragments thereof are provided. Also provided are isolated nucleic acids, recombinant vectors and host cells for making the antibodies and fragments. The antibodies and fragments can be used in therapeutic applications to treat, for example, autoimmune diseases, cancer, and graft rejection.