Antibody-drug conjugates in breast cancer: redefining targeted therapy
Chenxu Guo, Leif W. Ellisen
Chenxu Guo, Leif W. Ellisen
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Antibody-drug conjugates in breast cancer: redefining targeted therapy

Abstract

Antibody-drug conjugates (ADCs) have transformed the treatment landscape of breast cancer and redefined the conceptual distinction between targeted therapy and conventional chemotherapy. Originally conceived as “magic bullets” that selectively deliver cytotoxic warheads to antigen-expressing tumor cells, clinical and mechanistic evidence indicates that ADC activity depends on a broader interplay of target-dependent and target-independent mechanisms, including extracellular payload release, bystander killing, off-tumor uptake, and immune modulation. Here, we examine ADCs in breast cancer as a distinct therapeutic paradigm. We discuss how antigen biology, linker chemistry, payload features, and drug-to-antibody ratio collectively determine efficacy, toxicity, and therapeutic index. We then compare currently approved and emerging HER2- and TROP2-directed ADCs, highlighting how differences in linker stability, payload pharmacology, and bystander capacity can affect clinical outcomes in ADCs sharing the same target. We further discuss the biological basis and translational challenges of de novo and acquired resistance related to targets, payloads, and tumor microenvironmental constraints, as well as the implications of these mechanisms for biomarker development, sequencing rationales, and combination strategies with immune checkpoint inhibitors and DNA repair–targeting therapies. Finally, we outline future directions of ADC development, including expansion of the target space, novel payload modalities, and next-generation antibody and conjugation engineering.

Authors

Chenxu Guo, Leif W. Ellisen

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Figure 1

Distinct structural features and mechanisms of action of FDA-approved ADCs in breast cancer.

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Distinct structural features and mechanisms of action of FDA-approved AD...
Trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), datopotamab deruxtecan (Dato-DXd), and sacituzumab govitecan (SG) differ in target, linker chemistry, payload class, and drug-to-antibody ratio, which together shape intracellular processing, bystander activity, and downstream cytotoxic effects. T-DM1 carries the noncleavable maytansinoid payload DM1 and primarily requires antigen binding, internalization, lysosomal degradation, and intracellular release of a membrane-impermeable catabolite that disrupts tubulin dynamics and induces mitotic arrest, with minimal bystander killing. In contrast, T-DXd and Dato-DXd contain cleavable tetrapeptide linkers and membrane-permeable topoisomerase 1 inhibitor (TOP1i) payloads that can be released after cathepsin-mediated cleavage, diffuse into neighboring antigen-low or antigen-negative cells, and promote bystander killing. SG similarly delivers a TOP1i payload through a pH-sensitive linker that can undergo hydrolysis in acidic conditions, further supporting extracellular payload liberation and bystander effects.