Payload diversification: a key step in the development of antibody–drug conjugates

Abstract

Antibody–drug conjugates (ADCs) is a fast moving class of targeted biotherapeutics that currently combines the selectivity of monoclonal antibodies with the potency of a payload consisting of cytotoxic agents. For many years microtubule targeting and DNA-intercalating agents were at the forefront of ADC development. The recent approval and clinical success of trastuzumab deruxtecan (Enhertu®) and sacituzumab govitecan (Trodelvy®), two topoisomerase 1 inhibitor-based ADCs, has shown the potential of conjugating unconventional payloads with differentiated mechanisms of action. Among future developments in the ADC field, payload diversification is expected to play a key role as illustrated by a growing number of preclinical and clinical stage unconventional payload-conjugated ADCs. This review presents a comprehensive overview of validated, forgotten and newly developed payloads with different mechanisms of action.

The Biocatalysis in Cancer Therapy

“…For most ADCs, the cytotoxic small molecules must be released once the ADC is inside the target. 206 The release of cytotoxic small molecules in vivo is closely related to the type of linker and the way of coupling.…”

“… Such immunoconjugates combine the targeting capabilities of monoclonal antibodies with the antitumor potency of cytotoxic small molecules. For most ADCs, the cytotoxic small molecules must be released once the ADC is inside the target . The release of cytotoxic small molecules in vivo is closely related to the type of linker and the way of coupling.…”

Lipoic Acid Ligase A‐Mediated Ligation: Mechanism, Applications, and Emerging Innovations in Bioconjugation

“…[75] In addition, the application of these enzymatic conjugation methods to ADCs must keep pace with the evolution of payload diversity. [109] Many well-known compounds have been utilized as ADC payloads in organic syntheses. Over time, innovative chemical interactions and sophisticated synthetic approaches have generated a wide array of natural products with potential payload applications.…”

Platinum–Acridine Agents with High Activity in Cancers Expressing the Solute Carrier MATE1 (SLC47A1)

“…One recent discovery involves the putative DNA/RNA helicase Schlafen 11 ( SLFN11 ), which sensitizes tumor tissue to topoisomerase I (topo I) poisons and other DNA-directed agents. − The latter class of drugs is now also being utilized as payloads in antibody–drug conjugates (ADCs) directed at tumor-specific antigens. Trastuzumab deruxtecan (Enhertu) and sacituzumab govitecan (Trodelvy) are examples of two recently FDA-approved ADCs containing topo I poisons as targeted cytotoxic payloads . These developments highlight two important future roles DNA-targeted anticancer drugs will play in precision oncology …”

“…Trastuzumab deruxtecan (Enhertu) and sacituzumab govitecan (Trodelvy) are examples of two recently FDAapproved ADCs containing topo I poisons as targeted cytotoxic payloads. 7 These developments highlight two important future roles DNA-targeted anticancer drugs will play in precision oncology. 2 DNA-targeted agents that can overcome resistance to existing therapies, by virtue of their distinct mechanisms at the genome level, continue to attract major attention.…”