The Potential of Topoisomerase Inhibitor-Based Antibody-Drug Conjugates

Abstract

DNA topoisomerases are essential enzymes that stabilize DNA supercoiling and resolve entanglements. Topoisomerase inhibitors have been widely used as anti-cancer drugs for the past 20 years. Due to their selectivity as topoisomerase I (TOP1) inhibitors that trap TOP1 cleavage complexes, camptothecin and its derivatives are promising anti-cancer drugs. To increase accumulation of TOP1 inhibitors in cancer cells through the targeting of tumors, TOP1 inhibitor antibody-drug conjugates (TOP1-ADC) have been developed and marketed. Some TOP1-ADCs have shown enhanced therapeutic efficacy compared to prototypical anti-cancer ADCs, such as T-DM1. Here, we review various types of camptothecin-based TOP1 inhibitors and recent developments in TOP1-ADCs. We then propose key points for the design and construction of TOP1-ADCs. Finally, we discuss promising combinatorial strategies, including newly developed approaches to maximizing the therapeutic potential of TOP1-ADCs.

Keywords: anti-cancer drug; antibody–drug conjugates; targeted drug delivery; topoisomerase 1; topoisomerase inhibitor.

Figure 1

TOP1 and TOP1 inhibitor mechanism. (A) TOP1 forms 3′-phosphotyrosine bonds, allowing the cut DNA strand to rotate about the intact one, thus relaxing DNA supercoiling. (B) A TOP1 inhibitor binds at the TOP1 enzyme–DNA interface to prevent DNA re-ligation and to lock the enzyme into TOP1cc. The TOP1 inhibitor thus generates DNA damage and, ultimately, cell death.

Figure 2

Chemical structure of (A) camptothecin, and its derivatives: (B) topotecan, (C) irinotecan, (D) SN-38, (E) belotecan, (F) exatecan, and (G) deruxtecan.

Figure 3

Schematic illustration of the therapeutic mechanism of TOP1-ADC.

Figure 4

Chemical structures of linkers for antibody–drug conjugation. (A) SMCC linker, (B) hydrazone linker, (C) disulfide linker, (D) CL2A linker, (E) β-glucuronide linker, (F) Val-Cit (VC) linker, (G) Gly-Gly-Phe-Gly (GGFG) linker. (A) is a non-cleavable linker, and (B–G) are cleavable linkers. Green- and brown-colored icons represent TOP1 inhibitor and antibody, respectively.

Figure 5

Conjugation sites of TOP1 inhibitors for linker attachment and the chemical structure of the cognate TOP1-ADC. (A) hydroxyl group in (i)-ring of SN-38 structure, (B) SN-38-based TOP1-ADC, (C) hydroxyl group in (i)-ring and amine group in (ii)-ring of exatecan, and (D) exatecan derivate (Dxd)-based TOP1-ADC. The antibody is depicted as a brown-colored icon.