Prospects for the Use of Antibody-Drug Conjugates in Cancer Therapy

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Abstract

Today, cancer continues to be one of the most dangerous diseases, annually causing the deaths of >9 million people in the world. Therefore, new and more effective methods of cancer therapy are in demand. Monoclonal antibody-based immunotherapy has already shown its effectiveness; and antibody-drug conjugates (ADC), as one of its successful variants, have significant and not yet fully realized potential. ADCs are monoclonal antibodies bound by linkers to cytotoxic drugs. In many clinical trials and already in standard clinical practice ADCs have demonstrated significant advantages over combination therapy with unmodified antibodies and chemotherapy drugs. Due to new achievements in the field of molecular immunology and biotechnology, the potential of ADCs is assessed as a breakthrough, which will allow them to become the most sought-after anticancer drugs in the coming years. Owing to ADC, it has become possible to deliver drugs to tumor cells in a targeted manner without significant toxic effects on healthy tissues and organs. To date, 15 ADC drugs have been approved worldwide for use in clinic, and more than a hundred more drugs of this class are at various stages of clinical trials. At the same time, therapy using ADC is associated with certain side effects and limited efficacy, and therefore there is a need to develop more advanced conjugates. This review examines the history of the development of ADC as a therapeutic class of drugs, their structure, targets and mechanism of action. It also outlines the prospects and directions for further development of ADCs.

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About the authors

A. O. Makarova

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences; Lomonosov Moscow State University

Email: khol@mail.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997; Leninskie Gory 1, Moscow, 119991

E. V. Svirshchevskaya

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences

Email: khol@mail.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997

M. M. Titov

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences

Email: khol@mail.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997

S. M. Deyev

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences; Sechenov First Moscow State Medical University; National Research Center “Kurchatov Institute”

Email: khol@mail.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997; ul. Trubetskaya 8/2, Moscow, 119992; pl. Kurchatova 1, Moscow, 123182

R. V. Kholodenko

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences; Real Target LLC

Author for correspondence.
Email: khol@mail.ru
Russian Federation, ul. Tekstilshchikov 3/3, Troitsk, Moscow Region, 108841

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2. 1. Schematic structure of an ADC consisting of a monoclonal antibody, a linker, and a cytotoxic drug. The drawing was created using the Bio Reader program (https://www.biorender.com /).

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3. Fig. 2. The mechanism of action of ADC. Internalization of the ADC–receptor complex and formation of the early endosome (1). Cleavage of ADC by acid hydrolases as a result of fusion of the late endosome with the lysosome (2). Release of the drug (3). Cytotoxic effect of the drug on cellular structures (in this case, DNA or microtubules) (4). In some cases, the effectiveness of therapy using ADC decreases due to the binding of the antibody to the neonatal Fc receptor (FcRn) in the endosome; in this case, ADC is recycled into the extracellular space (2*). The drawing was created using the BioRender program (https://www.biorender.com /).

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4. Fig. 3. The main methods of conjugation of mAt and drug in the composition of ADC and their corresponding average DAR values. The drawing is modified based on [49].

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5. 4. Schematic structure of IgG subclasses, as well as various antibody formats used in the composition of ADC, for targeted drug delivery. The drawing was created using the Bio Reader program (https://www.biorender.com /).

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6. Fig. 5. GD2 ganglioside structure. The drawing is modified based on [78].

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