Antibody-Drug Conjugates: How Targeted Cancer Therapies Are Expanding Beyond Breast Cancer

What Are Antibody-Drug Conjugates and How Do They Work?

Antibody-drug conjugates represent a sophisticated approach to cancer treatment that has evolved significantly since the first ADC, gemtuzumab ozogamicin (Mylotarg), was approved by the FDA for acute myeloid leukemia. The concept is elegantly simple: attach a powerful cytotoxic drug to an antibody that recognizes a specific protein on cancer cells. When the ADC binds to its target, the entire complex is internalized by the cancer cell, where the chemotherapy payload is released to destroy it from within.

The technology hinges on three critical components — the antibody, the linker, and the cytotoxic payload. Advances in linker chemistry have been particularly transformative. Earlier ADCs suffered from premature payload release in the bloodstream, causing off-target toxicity. Modern cleavable linkers are designed to remain stable in circulation but release their payload efficiently once inside the acidic environment of a tumor cell's lysosome. This precision is what gives ADCs their favorable therapeutic index compared to traditional chemotherapy.

Which Cancers Are Being Treated With New ADC Therapies?

The landmark expansion of trastuzumab deruxtecan (Enhertu), developed by Daiichi Sankyo and AstraZeneca, into HER2-low breast cancer marked a paradigm shift. The DESTINY-Breast04 trial, published in The New England Journal of Medicine, demonstrated significant improvements in progression-free and overall survival in patients with HER2-low metastatic breast cancer — a population previously considered HER2-negative and ineligible for HER2-targeted therapy. This effectively expanded the treatable population by millions of patients worldwide.

Beyond breast cancer, the DESTINY-Lung series of trials has established trastuzumab deruxtecan as a treatment option for HER2-mutant non-small cell lung cancer. Meanwhile, sacituzumab govitecan (Trodelvy), which targets Trop-2, has gained approvals in triple-negative breast cancer and urothelial carcinoma. Enfortumab vedotin (Padcev), targeting Nectin-4, has become a standard of care in advanced bladder cancer, particularly in combination with pembrolizumab. The breadth of targets and tumor types under investigation suggests ADCs may eventually become a backbone of treatment across most solid tumors.

What Are the Side Effects and Limitations of ADC Therapy?

Despite their targeted mechanism, ADCs are not without toxicity. Because the cytotoxic payload can affect rapidly dividing normal cells once released, side effects such as neutropenia, anemia, nausea, and fatigue are common across the ADC class. The specific side effect profile varies depending on the payload — ADCs carrying topoisomerase I inhibitors (like deruxtecan) differ from those using microtubule inhibitors (like vedotin) or DNA-damaging agents.

Interstitial lung disease (ILD) is the most concerning class-specific toxicity associated with trastuzumab deruxtecan, occurring in a small percentage of patients but carrying significant morbidity. Clinical guidelines now recommend baseline and periodic lung imaging, along with prompt treatment interruption at the first signs of respiratory symptoms. Ongoing research into next-generation ADCs focuses on improving the therapeutic window through novel targets, more selective linkers, and bystander-effect optimization — where the released payload can also kill neighboring tumor cells that may not express the target antigen.