Antibody-Drug Conjugates: The New Frontier of Chemotherapy

Abstract

In recent years, antibody-drug conjugates (ADCs) have become promising antitumor agents to be used as one of the tools in personalized cancer medicine. ADCs are comprised of a drug with cytotoxic activity cross-linked to a monoclonal antibody, targeting antigens expressed at higher levels on tumor cells than on normal cells. By providing a selective targeting mechanism for cytotoxic drugs, ADCs improve the therapeutic index in clinical practice. In this review, the chemistry of ADC linker conjugation together with strategies adopted to improve antibody tolerability (by reducing antigenicity) are examined, with particular attention to ADCs approved by the regulatory agencies (the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA)) for treating cancer patients. Recent developments in engineering Immunoglobulin (Ig) genes and antibody humanization have greatly reduced some of the problems of the first generation of ADCs, beset by problems, such as random coupling of the payload and immunogenicity of the antibody. ADC development and clinical use is a fast, evolving area, and will likely prove an important modality for the treatment of cancer in the near future.

Keywords: Antibody-Drug Conjugate; Mabs; cancer therapy; cross-linking; drug targeting; payload.

Figure 1

Schematic representation of various types of antibody-drug conjugates (ADCs) and their components.

Figure 2

Schematic illustration of the mechanism of drug delivery and release mediated by ADCs.

Figure 3

Available cleavable linkers in ADC (A) Disulfide linker, cleaved by reducing agents; (B) cathepsin B responsive linker, cleaved by Cathepsin B; (C) glycosidase-sensitive linker, cleaved by gluconidase; (D) hydrazone linker, cleaved by acidic environment.

Figure 4

PABC, p-aminobenzyl carbamate, CAS#:918132-66-8.

Figure 5

Mechanism of action of tubulin inhibitors payloads: polymerization promoters (microtubule stabilizers) and tubulin polymerization inhibitors (microtubule destabilizers). In the figure are two exemplifying drugs acting on microtubule formation: auristatins alters the formation of microtubules by binding on the β-subunit of α-β tubulin dimers; thus, producing uncontrolled growth of microtubules. Maytansines, on the contrary, stop tubulin dimers formation impairing the production of mature microtubules.

Figure 6

Classical microtubule-targeting agents: maytansinoids (left) and auristatin families (right).

Figure 7

Other microtubule-targeting agents.

Figure 8

The four main mechanisms of action of DNA-damaging agents: DNA double-strand breakers, DNA alkylators, DNA intercalators, and DNA cross-linkers. DNA-damaging agents. These drugs can act at any phase of tumor cell life cycle.

Figure 9

Examples of DNA-damaging drug payloads.

Figure 10

Summary diagram of the different classes of cytotoxic molecules used in ADC construction.

Figure 11

Main reactions used in the cross-linking procedures. (A) Lysine amide coupling, (B) Maleimide Alkylation, and (C) thiol-reactive conjugation.