Antibody–drug conjugates: the evolving field of targeted chemotherapy for breast cancer treatment

Abstract

Antibody–drug conjugates (ADCs) are a class of antineoplastic agents whose structure is composed of three main components: a monoclonal antibody (mAB) targeting a specific target antigen, a cytotoxic payload, and a linker binding the antibody to the payload. By combining the specificity of mABs with the high potency of the payloads, ADCs constitute a smart drug delivery system with improved therapeutic index. After recognition and binding of the mAB to its target surface antigen, ADCs are internalized by endocytosis by the tumor cell, releasing the payloads into the cytoplasm, where they exert their cytotoxic activity, eventually leading to cell death. The composition of some of the new ADCs confers additional functional properties that allow expanding their activity to neighboring cells not expressing the target antigen, constituting a valuable strategy to overcome tumor heterogeneity. Some of these ‘off-target effects’, such as the bystander effect, are possibly the mechanism underlying the antitumor activity demonstrated in patients with low expression of the target antigens, which represents an important paradigm shift in anticancer targeted therapy. Three ADCs are currently approved for the treatment of breast cancer (BC); two anti-HER2 (human epidermal growth factor receptor 2) ADCs (trastuzumab emtansine and trastuzumab deruxtecan); and one Trop-2-targeted ADC (sacituzumab govitecan). Based on the unprecedented efficacy data demonstrated by these agents, ADCs have been incorporated as part of standard regimens for all subtypes of advanced BC, as well as for high-risk early HER2-positive BC. Despite the remarkable advances, several hurdles still remain to overcome, including the development of reliable biomarkers for patient selection, prevention, and management of potentially severe toxicities, ADC resistance mechanisms, post-ADC resistance patterns, and optimal treatment sequencing and combinations. In this review, we will summarize the currently available evidence related to the use of these agents, as well as explore the current landscape of ADC development for BC treatment.

Monoclonal War: The Antibody Arsenal and Targets for Expanded Application

“…The ADC is administered into the blood, where the antibody component binds to cancer-specific surface antigens. Endocytosis of the ADC releases the cytotoxic payload, which disrupts DNA regulatory proteins and causes cancer cell death [30]. A challenge in designing ADCs is the trade-off between antigen affinity and tumor penetration.…”

Emerging non-antibody‒drug conjugates (non-ADCs) therapeutics of toxins for cancer treatment

“…ADCs bring together the targeting advantages of monoclonal antibodies (mAbs) with the cytotoxic potential of small molecules to enhance specific drug delivery in tumor cells through the antibody-antigen interaction while sparing healthy tissues and/or cells from toxic damage 6 , 7 , 8 . Once mAbs selectively bind to the target antigen on the tumor cell, ADCs are internalized into cells and the payloads are released with the linker breaking or antibody hydrolysis, followed by free drug disrupting the function of the corresponding cellular structure 9 . The clinical results of ADCs are undeniably encouraging and preferable ADCs are designed continuously, but they still have shortcomings, including low drug loading capacity, poor delivery efficiency, possible immunogenicity, high cost of ADCs production, and low potential to penetrate solid tumors 10 , 11 , 12 , 13 .…”

Safety Profile of the Trastuzumab-Based ADCs: Analysis of Real-World Data Registered in EudraVigilance

“…T-DM1 has low payload membrane permeability and is bound by a thioether non-cleavable linker, while T-DXd has high payload membrane permeability and is bound by a cleavable tetrapeptide-based linker. Between the two, only T-DXd presents the bystander effect [24] that leads to cell death of the neighboring tumor cells by amplifying the activity of the cytotoxic drug [25] (Figure 2b). Regarding their efficiency, a study performed by Cortes et al showed that the risk of disease progression or death was reduced in patients treated with T-DXd compared to T-DM1 [29].…”