New Antibody–Drug Conjugates in Breast Cancer

Breast cancer has the highest prevalence of all cancers and is second only to lung cancer in cancer fatality rates in women in the United States.¹ Sadly, the majority of women with metastatic breast cancer will not survive their disease.¹ New therapies are urgently needed to give these patients more hopeful outcomes.

Antibody–drug conjugates (ADCs) are a form of cancer therapy that utilizes the specificity of monoclonal antibodies toward cellular antigens to deliver potent cytotoxic drugs in a precise and selectively targeted manner.² This results in potentially higher efficacy and less toxicity than conventional chemotherapy.² ADCs comprise an antibody construct coupled to a payload (usually a cytotoxic agent) by a linker moiety.¹ The antibody binds to overexpressed or specifically expressed target tumor antigens, the ADC is internalized, and the payload is released.¹ Release of the payload can be caused by proteolytic degradation of the whole ADC molecule or cleavage of the linker moiety due to extracellular or intracellular conditions.¹

Two new ADCs containing a topoisomerase I inhibitor payload are recent additions to available breast cancer treatments.³ Sacituzumab govitecan-hziy (SG) is a first-in-class anti–Trop-2 ADC approved for pretreated metastatic triple-negative breast cancer.³ Trastuzumab deruxtecan (T-DXd) has been approved for HER2-positive advanced breast cancer.³

SG consists of an anti–Trop-2 monoclonal antibody hRS7 IgG1κ and a cleavable CL2A linker coupled to the cytotoxic payload SN-38.¹ SN-38 is an active metabolite of the topoisomerase I inhibitor irinotecan.¹ SG has a high drug-to-antibody ratio of 7.6 molecules of SN-38 to each monoclonal antibody.¹ This results in delivery of high concentrations of cytotoxic agent.¹

T-DXd contains an anti-HER2 monoclonal antibody with an equivalent amino acid sequence to trastuzumab.¹ It is linked to a potent topoisomerase I inhibitor payload (an exatecan derivative) via a cleavable tetrapeptide-based link.¹ T-DXd has a high drug-to-antibody ratio of 8 molecules of the exatecan derivative to each monoclonal antibody.¹

Considering both SG and T-DXd are powerfully active agents when used as monotherapy, they are expected to have a significant effect on treatment standards.³ The likelihood of the indications being expanded is high, and several studies are assessing a transition to earlier lines and use in combination therapy.³

References

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