Antibody-Drug Conjugates for the Treatment of HER2-Positive Breast Cancer

Abstract

Human epidermal growth factor receptor 2 (HER2) receptor tyrosine kinase is overexpressed in 20-30% of breast cancers and is associated with poor prognosis and worse overall patient survival. Most women with HER2-positive breast cancer receive neoadjuvant chemotherapy plus HER2-targeted therapies. The development of HER2-directed therapeutics is an important advancement in targeting invasive breast cancer. Despite the efficacy of anti-HER2 monoclonal antibodies, they are still being combined with adjuvant chemotherapy to improve overall patient outcomes. Recently, significant progress has been made towards the development of a class of therapeutics known as antibody-drug conjugates (ADCs), which leverage the high specificity of HER2-targeted monoclonal antibodies with the potent cytotoxic effects of various small molecules, such as tubulin inhibitors and topoisomerase inhibitors. To date, two HER2-targeting ADCs have been approved by the FDA for the treatment of HER2-positive breast cancer: Ado-trastuzumab emtansine (T-DM1; Kadcyla^®) and fam-trastuzumab deruxtecan-nxki (T-Dxd; Enhertu^®). Kadcyla and Enhertu are approved for use as a second-line treatment after trastuzumab-taxane-based therapy in patients with HER2-positive breast cancer. The success of ADCs in the treatment of HER2-positive breast cancer provides novel therapeutic advancements in the management of the disease. In this review, we discuss the basic biology of HER2, its downstream signaling pathways, currently available anti-HER2 therapeutic modalities and their mechanisms of action, and the latest clinical and safety characteristics of ADCs used for the treatment of HER2-positive breast cancer.

Keywords: ADC; Enhertu; HER2; T-DM1; antibody drug conjugate; breast cancer; cancer; monoclonal antibody; therapeutics; trastuzumab.

Figure 1

Overview of the HER2 signaling pathway. Unlike the other EGFR family of receptors, HER2 does not bind to any known ligands. Instead, HER2 is activated following heterodimerization with other activated EGFR family of receptors or by heterodimerization with activated HER2 receptors. Receptor dimerization leads to the phosphorylation of tyrosine residues and resultant signal transduction. PI3K/AKT, RAS/MEK/MAPK, JAK/STAT, and PKC are the most common signaling pathways through which several downstream cascades are activated, promoting numerous effects, including cell proliferation, survival, differentiation, angiogenesis, and invasion. Moreover, activated PI3K/AKT also leads to the degradation of cell-cycle inhibitor p27^Kip1 and thus promotes cell-cycle progression. EGF, Epidermal growth factor; HB-EGF, heparin-binding epidermal growth factor; TGF, tumor growth factor; NRG, neuregulin.

Figure 2

Schematic diagram of an ADC showing the general structure and favorable characteristics. The antibody contains antigen-binding sites (F_ab) engineered to recognize target antigens. Payloads are connected to the antibody via linkers.

Figure 3

Antibody-drug conjugate mechanism of action. Once the ADC is administered, (1) it is released into the bloodstream. (2) The antibody portion of the ADC binds to overexpressed target tumor antigen/receptor (e.g., HER2). (3) Upon binding, the ADC-receptor complex undergoes receptor-mediated endocytosis, leading to the formation of endosomes (4). Within the lysosome, (5) the ADC-receptor complex is degraded, and the linker is cleaved, leading to the release of cytotoxic payloads (6). Depending on the type of payload used, (7) it will cause cell death either through DNA damage or microtubule disruption. Additionally, (8) payloads that have a membrane-permeable nature will exert the same cytotoxic effect on neighboring cells through a process known as the bystander effect, regardless of their antigen expression.