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 4

Future generations of ADCs in breast cancer.

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Future generations of ADCs in breast cancer. Next-generation ADC develop...
Next-generation ADC development in breast cancer is advancing along three major axes. (A) Target space expansion extends beyond established tumor-associated antigens to include novel tumor cell targets, such as HER3, Nectin-4, mesothelin (MSLN), and folate receptor alpha (FOLR1), as well as nontumor antigens expressed by cancer-associated stromal compartments, including fibroblasts and endothelial cells, exemplified by LRRC5, FAP, TEM8, and CD105. (B) Novel payload modalities broaden the functional repertoire of ADCs beyond conventional cytotoxic warheads to include immune-stimulating payloads (for example, STING and TLR7/8 agonists), transcription-directed payloads (for example, α-amanitin), oligonucleotide-based payloads (for example, siRNA), targeted protein-degrading payloads (including proteolysis-targeting chimeras [PROTACs] and molecular glues), immunotoxins (for example, PE24 and PE25), radionuclide-based payloads (for example, 177Lu and 67Cu), and photosensitizer-based payloads (for example, IR700). (C) Antibody and conjugation engineering aims to improve selectivity, stability, and therapeutic index through biparatopic ADCs, dual-payload ADCs, probody ADCs, Fc engineering, bispecific ADCs, and site-specific conjugation strategies, including engineered cysteines, glycan remodeling, Fc-affinity peptide-mediated conjugation, unnatural amino acids, and enzymatic ligation.