New Antibody–Drug Conjugates in Breast Cancer

Breast cancer is one of the most common cancers among women in the United States, and second only to lung cancer in terms of cancer death rates.¹ Unfortunately, the majority of women who are diagnosed with metastatic breast cancer will die from it.² Progress has been made with new antibody–drug conjugates (ADCs), which have provided these patients some hope.

ADCs are an interesting new type of cancer treatment that can employ monoclonal antibodies’ affinity for cellular antigens to deliver strong cytotoxic medicines in a precise and selectively targeted manner.³ As a result, compared with traditional chemotherapy, it has a higher efficacy and lower toxicity. An antibody construct is linked to a payload (typically a cytotoxic chemical) by a linker moiety. The ADC is internalized, and the payload is released once the antibody attaches to overexpressed or precisely expressed target tumor antigens.² Proteolytic breakdown of the whole ADC molecule or cleavage of the linker moiety owing to extracellular or intracellular circumstances can trigger payload release.²

Sacituzumab govitecan-hziy comprises an anti–Trop-2 monoclonal antibody hRS7 IgG1κ and a cleavable CL2A linker coupled to the cytotoxic payload SN-38.^1,2 SN-38 is an active metabolite of the topoisomerase I inhibitor irinotecan.² Sacituzumab govitecan has a high drug-to-antibody ratio of 7.6 molecules of SN-38 to each monoclonal antibody.¹ This causes delivery of high concentrations of cytotoxic agent to the cancer cells.²

Trastuzumab deruxtecan comprises a monoclonal anti-human epidermal growth factor receptor 2 antibody with the same amino acid sequence as trastuzumab.² A cleavable tetrapeptide-based connection connects it to a strong topoisomerase I inhibitor payload (an exatecan derivative).² Trastuzumab deruxtecan has a drug-to-antibody ratio of 8 molecules of exatecan derivative per monoclonal antibody, which is a high value.²

Given that sacituzumab govitecan and trastuzumab deruxtecan are highly active monotherapies, they are predicted to have a major impact on treatment guidelines.¹ There is a good chance that the indications will be broadened, and several trials are looking into switching to earlier lines and using them in combination therapy.¹ ADCs are at the forefront of breast cancer treatment innovation and efficacy.³ Research efforts are continuing in an attempt to identify new targets and, as a result, improve patient outcomes.³

References

1. Adams E, Wildiers H, Neven P, Punie K. Sacituzumab govitecan and trastuzumab deruxtecan: two new antibody–drug conjugates in the breast cancer treatment landscape. ESMO Open. 2021;6:100204.
2. Barroso-Sousa R, Tolaney SM. Clinical development of new antibody–drug conjugates in breast cancer: to infinity and beyond. BioDrugs. 2021;35:159-174.
3. Nicolò E, Zagami P, Curigliano G. Antibody-drug conjugates in breast cancer: the chemotherapy of the future? Curr Opin Oncol. 2020;32:494-502.