Mechanisms of Resistance to Antibody-Drug Conjugates.

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.

Current and Emerging Role of Antibody-Drug Conjugates in HER2-Negative Breast Cancer.

Antibody-drug conjugates (ADCs) are rapidly evolving therapies that are uniquely able to deliver potent chemotherapy specifically to cancer cells while largely sparing normal cells. ADCs have 3 components: (1) antibody targeted to a tumor-involved antigen, (2) cytotoxic payload, and (3) linker that connects the cytotoxic agent to the antibody. Once the antibody binds the target on the cell surface, the ADC is incorporated into the cell via receptor-mediated endocytosis. Inside the cells, the linker is cleaved in the lysosome and the payload is then released intracellularly. This article will review ADCs in clinical development for HER2-negative metastatic breast cancer.

Antibody-Drug Conjugates in Breast Cancer: Spotlight on HER2.

ABSTRACT: Antibody-drug conjugates (ADCs) are composed of monoclonal antibodies linked to a cytotoxic payload, enabling targeted delivery of more potent chemotherapy. In the past decade, there has been rapid development of ADCs aimed at different types of breast cancer. The success of the monoclonal antibody trastuzumab has led to the evolution of several ADCs targeting HER2-positive breast cancer. Trastuzumab-emtansine, the first approved ADC targeting HER2-positive breast cancer, has become standard of care for patients with high-risk early-stage HER2-positive breast cancer who have residual disease after neoadjuvant chemotherapy. More recently, the observation of the bystander effect, in which ADCs target both antigen-positive cells and adjacent antigen-negative cells, has led to the reclassification of "HER2-low" breast cancer and the development of trastuzumab-deruxtecan to target this population. This article reviews the history of HER2-directed ADCs in breast cancer as well as ongoing ADCs in development.