Investigational antibody-drug conjugates in clinical trials for the treatment of breast cancer

摘要

Antibody-drug conjugates (ADCs) combine the selectivity of monoclonal antibodies (mAb) with the cytotoxicity of chemotherapy. This allows delivery of the 'payload' directly into cancer cells expressing the target antigen and, in some cases, 'bystander killing' of adjacent antigen-negative cells following apoptosis of ADC-containing cells; an effect which can overcome intra-tumoral heterogeneity (Figure 1). The success of ADCs is dependent upon selection of a cancer cell-specific target antigen, a linker which is sufficiently stable to prevent premature release of the payload prior to reaching the target, but which can be cleaved once internalized, and an effective cytotoxic ragent. Ideally, the mAb will also be capable of antibody-dependent cellular toxicity (ADCC) and/or complement-dependent cytotoxicity (CDC) to increase the efficacy. The specific lethality of these agents for antigenoverexpressing cancer cells and relative sparing of healthy, proliferating cells minimizes the severity of systemic side effects, making them a very appealing option in the breast cancer treatment paradigm. Although the first wave of these agents have been limited to HER2-positive breast cancer, using trastuzumab, a mAb already in routine clinical use, a variety of pain-breast cancer antigens have recently been identified (e.g. Trop-2) that are redefining the molecular classification of breast cancer, and can act as targets for new ADCs. This editorial will summarize the growing body of clinical evidence for licensed ADCs and explore the available data for experimental drugs in early phase development.