Extracellular vesicles as modifiers of antibody‐drug conjugate efficacy

Abstract

Antibody‐drug conjugates (ADCs) are a new class of anti‐cancer drugs that consist of a monoclonal antibody, a highly potent small‐molecule cytotoxic drug, and a chemical linker between the two. ADCs can selectively deliver cytotoxic drugs to cancer cells leading to a reduced systemic exposure and a wider therapeutic window. To date, nine ADCs have received marketing approval, and over 100 are being investigated in nearly 600 clinical trials. The target antigens of at least eight out of the nine approved anti‐cancer ADCs and of 69 investigational ADCs are present on extracellular vesicles (EVs) (tiny particles produced by almost all types of cells) that may carry their contents into local and distant cells. Therefore, the EVs have a potential to mediate both the anti‐cancer effects and the adverse effects of ADCs. In this overview, we discuss the mechanisms of action of ADCs and the resistance mechanisms to them, the EV‐mediated resistance mechanisms to small molecule anti‐cancer drugs and anti‐cancer monoclonal antibodies, and the EVs as modifiers of ADC efficacy and safety.

Impact of Non-Coding RNAs on Chemotherapeutic Resistance in Oral Cancer

“…Thus, EVs are appreciated as essential mediators of cell-to-cell communication. In the field of cancer biology, EVs have been found to play crucial roles in cancer metastasis [ 189 ] and drug resistance [ 190 , 191 , 192 , 193 , 194 , 195 ]. In oral cancer, EVs also mediate drug resistance by transferring their cargoes to recipient cells [ 196 , 197 , 198 , 199 , 200 , 201 , 202 ].…”

Anti-tumour drugs of marine origin currently at various stages of clinical trials (review)

“…Unlike regular chemotherapeutic dugs, antibody-drug conjugates are a promising and most dynamically developing class of drugs, and have broad therapeutic range due to effective and specific transport of drug to antigen-expressing tumour cells (Mukherjee et al, 2019;Khongorzul et al, 2020). The FDA currently allow nine of them to be used, and over 80 of them, which are aimed at over 50 various antibodies, are at different phases of 600 clinical trials (Boni, et al, 2020, Barok et al, 2021. Despite the high efficiency and promising character of ADCs of the last generation, their synthesis is associated with certain difficulties such as humanization of antibodies, complexity of the processes of modification and conjugation with beneficial load.…”

Antibody-Antineoplastic Conjugates in Gynecological Malignancies: Current Status and Future Perspectives

“…Then, the antineoplastic drug is released and exerts its anticancer activity [ 12 , 14 ]. Some antibodies have also an antitumor effect per se which improving the overall antitumor efficacy [ 15 ]. This is the case of trastuzumab, approved for the treatment of human epidermal growth factor receptor-2 (HER-2) positive breast and gastric tumors [ 16 ], and that it is present in two approved ADCs: Kadcyla ® and Enhertu ® .…”

“…A166 is an ADC consisting of an anti-HER-2 monoclonal antibody conjugated to duostatin-5, a MMAF derivative [ 15 , 137 ]. A phase I-II clinical study is underway in patients with HER-2 positive solid tumors, including patients with cervical cancer (NCT03602079).…”