Repurposing Legacy Cytotoxics May Define the Next Generation of ADCs : Trends in Cancer | May 2026

Introduction

Antibody–drug conjugates (ADCs) have transformed oncology by enabling selective delivery of potent cytotoxic agents directly to tumor cells. Recent successes, particularly with trastuzumab deruxtecan, have expanded the role of ADCs across multiple solid tumors and validated the concept of targeted payload delivery as a major therapeutic platform.

Problem Statement

Despite rapid clinical expansion, most ADC development programs increasingly rely on a narrow group of payload classes—primarily topoisomerase I inhibitors and microtubule toxins. This mechanistic convergence raises concerns regarding overlapping toxicities, emerging cross-resistance and limited innovation in payload diversity. At the same time, many historically abandoned cytotoxic agents may have failed not because of inadequate antitumor activity, but because systemic exposure rendered them intolerable as free drugs.

Summary

This perspective proposes a major conceptual shift in ADC development by advocating systematic repurposing of legacy cytotoxic compounds as next-generation ADC payloads. Using trastuzumab deruxtecan as the central model, the authors argue that ADC success depends less on maximal intrinsic potency and more on pharmacologic compatibility with targeted delivery. They introduce a five-pillar framework for payload selection emphasizing proliferation-restricted cytotoxicity, pharmacokinetic “softness,” sustained intracellular target engagement and controlled bystander effects rather than ultrapotent lethality alone. The review highlights multiple underexplored payload classes—including antifolates, nucleoside analogs, kinesin spindle protein inhibitors, noncamptothecin topoisomerase inhibitors and DNA intercalators—that may become clinically viable when delivered through antibody-directed platforms. Importantly, many of these compounds already possess substantial historical pharmacology and toxicity data, potentially accelerating translational development. The authors also emphasize that future ADC innovation will require broader mechanistic diversification to avoid class-wide resistance and toxicity saturation associated with current TOP1-dominant strategies. Overall, this article reframes ADC payload discovery from a potency-driven paradigm toward a systems-level pharmacologic design strategy focused on tumor-selective exposure and biologic precision.