Anti-Nectin-4 ADC Epitope Targeting for Lower Skin Toxicity
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Solution Overview
Problem
Existing anti-Nectin-4 antibodies exhibit high binding affinity to both tumor cells and normal keratinocytes, leading to increased skin toxicity and reduced therapeutic index in cancer treatment.
Innovation Solution
Development of monoclonal antibodies and antibody-drug conjugates that specifically target a discontinuous epitope on Nectin-4, comprising amino acids D57, S58, E60, P133, G135, F137, Q138, and R140, with optimized variable heavy and light chain regions to enhance selectivity and reduce binding to keratinocytes, coupled with a drug conjugate like topoisomerase inhibitors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing anti-Nectin-4 antibodies are used to target tumor cells, then anti-cancer activity is achieved, but skin toxicity increases due to binding to keratinocytes
Solution Approach 1:
The patent applies local quality by designing antibodies with differentiated binding characteristics for different tissues. The antibody specifically targets Nectin-4 on tumor cells while minimizing binding to keratinocytes, creating tissue-specific activity profiles that eliminate skin toxicity while maintaining anti-cancer efficacy through selective epitope recognition
Solution Approach 2:
The patent employs parameter changes by modifying the antibody's binding affinity parameters through epitope selection. By targeting a specific discontinuous epitope on Nectin-4, the antibody achieves high affinity for tumor cells while reducing affinity for keratinocytes, thereby changing the binding parameter profile to eliminate skin toxicity
2Productivity
If anti-Nectin-4 antibodies bind to tumor cells with high affinity, then treatment efficacy is improved, but therapeutic index decreases due to non-specific binding
Solution Approach 1:
The patent achieves local quality differentiation by creating an antibody with selective binding properties. The antibody exhibits high binding affinity specifically for Nectin-4 on tumor cells while demonstrating reduced binding to normal tissues, thereby improving therapeutic index through tissue-selective action rather than non-specific binding
Solution Approach 2:
The patent replaces non-specific mechanical binding with specific molecular recognition. By targeting a defined discontinuous epitope, the antibody uses precise molecular interaction mechanisms to achieve high specificity, replacing the non-specific binding mechanism that previously limited therapeutic index
Data Source
AI summary
The present invention relates to novel anti Nectin-4 antibodies and antibody-drug conjugates comprising these antibodies, as well as to the use thereof.