Nectin-4 Antibody–Drug Conjugates Targeting the VC1 Bridging Domain
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Solution Overview
Problem
Existing anti-Nectin-4 antibodies, such as Enfortumab vedotin, have limitations in therapeutic efficacy and safety, particularly in treating cancers like urothelial cancer, with high discontinuation rates due to progressive disease and adverse events, highlighting the need for improved anti-Nectin-4 therapies.
Innovation Solution
Development of anti-Nectin-4 antibodies or antibody fragments with specific binding domains, particularly targeting the VC1 bridging domain, and conjugation to cytotoxic agents via cleavable linkers, enabling intracellular delivery and enhanced therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing anti-Nectin-4 antibodies (e.g., Enfortumab vedotin) are used to treat cancer, then tumor cell targeting is achieved, but therapeutic efficacy is limited and adverse events occur leading to high discontinuation rates
Solution Approach 1:
The patent applies parameter changes by modifying the antibody structure to target a different domain (VC1 bridging domain instead of Ig-like V type domain) and changing the conjugation strategy (site-specific conjugation to cysteine residues). These parameter changes in the antibody-drug conjugate design improve therapeutic efficacy while reducing adverse events by enabling more controlled drug delivery to tumor cells
Solution Approach 2:
The patent employs local quality by introducing site-specific conjugation at particular cysteine residues (e.g., C234, C246, C258) within the antibody structure. This localized modification approach ensures uniform drug distribution and controlled release, improving therapeutic efficacy while minimizing off-target effects and adverse events
2Strength
If anti-Nectin-4 antibodies are conjugated to cytotoxic agents, then tumor cell killing is enhanced, but drug resistance develops in some cancers
Solution Approach 1:
The patent uses the VC1 bridging domain of Nectin-4 as an intermediary target that is less associated with drug resistance mechanisms. By targeting this specific domain and using site-specific conjugation, the antibody-drug conjugate achieves effective tumor cell killing while bypassing resistance pathways that develop against conventional ADCs targeting other domains
3Duration of action of moving object
If antibodies targeting the Ig-like V type domain are used, then internalization is maximized, but therapeutic limitations and resistance occur
Solution Approach 1:
The patent applies inversion by reversing the conventional approach: instead of targeting the Ig-like V type domain (which maximizes internalization but causes therapeutic limitations), the invention targets the VC1 bridging domain. This inverted strategy achieves effective tumor cell killing through alternative mechanisms while avoiding the therapeutic bottlenecks and resistance issues associated with V domain targeting
Data Source
AI summary
The invention relates to antibodies and antibody fragment that bind to Nectin-4 polypeptides. The invention also relates to antibody-drug conjugates that comprise the antibodies or antibody fragments, and to methods of making the conjugates, pharmaceutical compositions, and method of using them to diagnose, treat or prevent diseases, e.g. cancer characterized by Nectin-4 expressing tumor cells.