Mechanisms of Resistance to Antibody–Drug Conjugates

SIMPLE SUMMARY: Antibody–drug conjugates (ADCs) are a growing class of therapies that aim to delivery therapy more efficiently, with fewer side effects, than conventional chemotherapy. ADCs are composed of an antibody linked to a chemotherapy payload, allowing targeted delivery of the chemotherapy. In the last decade, several antibody–drug conjugates have improved treatment options in breast cancer. However, patients usually progress on these agents, and more research is needed into why this resistance occurs. Given the complex structure of antibody-drug conjugates, resistance may be related to changes in antigen expression, ADC processing, and the chemotherapy payload. This paper reviews the literature on the mechanisms of resistance to antibody–drug conjugates including pre-clinical and clinical studies in breast cancer and other malignancies. This review includes information on ADCs that have been approved for use in breast cancer and ADCs in development that seek to overcome the proposed mechanisms of resistance to improve treatment options for patients. ABSTRACT: Antibody–drug conjugates (ADCs), with antibodies targeted against specific antigens linked to cytotoxic payloads, offer the opportunity for a more specific delivery of chemotherapy and other bioactive payloads to minimize side effects. First approved in the setting of HER2+ breast cancer, more recent ADCs have been developed for triple-negative breast cancer (TNBC) and, most recently, hormone receptor-positive (HR+) breast cancer. While antibody–drug conjugates have compared favorably against traditional chemotherapy in some settings, patients eventually progress on these therapies and require a change in treatment. Mechanisms to explain the resistance to ADCs are highly sought after, in hopes of developing next-line treatment options and expanding the therapeutic windows of existing therapies. These resistance mechanisms are categorized as follows: change in antigen expression, change in ADC processing and resistance, and efflux of the ADC payload. This paper reviews the recently published literature on these mechanisms as well as potential options to overcome these barriers.