Beyond Conventional Adcs: Engineering The Next Generation of Antibody–Drug Conjugates For Cancer Therapy

Abstract

Antibody–drug conjugates (ADCs) are often optimized one component at a time even though clinical performance emerges from interactions among target density, internalisation, linker stability, payload mechanism, drug-to-antibody ratio (DAR), tumour penetration and resistance. This paper introduces the Multi-Parameter Adaptive ADC Engineering Framework (MAAEF), a prospective, falsifiable design-and-verification strategy for solid tumours with heterogeneous antigen expression. MAAEF combines dual-target recognition, tumour-responsive release, orthogonal dual payloads and site-specific DAR control in a seven-group factorial architecture. It pre-specifies construct-quality gates, antigen-stratified two-dimensional and three-dimensional assays, 12-cycle resistance evolution, molecular profiling and locked multi-objective model validation. Five normalized indices quantify linker selectivity, heterogeneity coverage, penetration, resistance suppression and safety; a composite score is permitted only after weight sensitivity and external validation. The framework’s immediate output is not a claim of therapeutic superiority, but an auditable route for determining whether integrated co-engineering produces synergistic benefit beyond component-level gains. By separating design targets from observations and requiring efficacy and developability to pass independent advancement gates, MAAEF addresses a recurrent source of overclaiming in preclinical ADC research. The protocol is intended to support reproducible candidate ranking, transparent failure analysis and clinically relevant go/no-go decisions before in-vivo translation.