TIM-3 Antibody Stability via CDR Mutation
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Solution Overview
Problem
Current TIM-3 antibodies lack stability and high affinity, hindering their therapeutic and diagnostic applications in TIM-3 related diseases, as they are prone to chemical modifications like deamidation, which reduces their bioavailability and effectiveness.
Innovation Solution
Development of a monoclonal antibody or antigen-binding fragment with specific CDR region sequences that provide high stability and affinity by competing with existing TIM-3 antibodies, incorporating amino acid mutations to prevent chemical modifications such as deamidation, and using recombinant vectors for production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional TIM-3 antibodies are used, then they can bind to TIM-3 antigen, but they lack stability and are prone to chemical modifications like deamidation
Solution Approach 1:
The patent applies parameter changes by modifying amino acid residues at specific positions (e.g., N55Q, Q58L, N97Q, Q100L mutations in CDR regions) to alter the chemical properties of the antibody. These parameter changes eliminate deamidation-prone asparagine and glutamine residues, thereby improving antibody stability and reducing chemical modifications while maintaining binding activity.
Solution Approach 2:
The patent converts the harmful effect of deamidation-prone amino acids into a benefit by deliberately introducing mutations that replace these residues. The harmful deamidation tendency is transformed into a design feature where the antibody sequence is pre-modified to resist degradation, turning a vulnerability into a stability advantage.
2Manufacturing precision
If TIM-3 antibody affinity is increased through CDR region optimization, then binding activity improves, but the antibody becomes more susceptible to chemical modifications
Solution Approach 1:
The patent applies local quality by making targeted amino acid substitutions specifically in the CDR regions where binding affinity is critical. By locally modifying only the necessary residues (e.g., positions 55, 58, 97, 100 in CDR2 and CDR3) while preserving the overall CDR structure, the antibody achieves high affinity without compromising stability in other regions.
Solution Approach 2:
The patent changes the chemical parameters of amino acids at critical binding positions, replacing deamidation-prone asparagine and glutamine with chemically stable alternatives. This parameter change maintains or enhances binding affinity while eliminating the harmful chemical degradation pathway.
3Productivity
If existing TIM-3 antibodies are used for therapeutic applications, then they can target TIM-3 positive cells, but their bioavailability is reduced due to instability
Solution Approach 1:
The patent applies preliminary action by pre-modifying the antibody sequence during the design phase to eliminate deamidation-prone residues before the antibody is produced and administered. This preliminary stabilization ensures that the antibody maintains its integrity and bioavailability throughout its therapeutic lifecycle, preventing in-vivo degradation.
Solution Approach 2:
The patent converts the potential harm of chemical degradation into a benefit by designing the antibody with inherent resistance to deamidation. This preliminary protection transforms what would be a stability problem into an advantage, ensuring higher bioavailability and sustained therapeutic effect.
Data Source
AI summary
A TIM-3 antibody, an antigen-binding fragment thereof, and medical uses thereof are described. More specifically, the present invention provides a rat-derived antibody containing a CDR region of the TIM-3 antibody, a chimeric antibody or a human-derived antibody thereof, and a pharmaceutical composition containing the TIM-3 antibody and the antigen-binding fragment thereof, as well as uses thereof serving as a drug. In particular, the present invention provides uses of a human-derived TIM-3 antibody in the preparation of drugs for treating TIM-3-related conditions.