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.

Keywords: Antibody–drug conjugates; Cytotoxic molecule; Payload; Topoisomerase 1 inhibitor.

Fig. 1

FDA approval of anticancer ADCs. ADCs are identified according to the nature of their payload: Microtubule-disrupting agents; DNA-targeting agents: Calicheamicin, pyrrolobenzodiazepine (PBD), topoisomerase 1 (TOPO 1) inhibitor

Fig. 2

Structure of topoisomerase I inhibitors-based ADCs. A FDA-approved ADCs and payloads (purple) and ADCs and payloads under clinical evaluation (blue). B Topoisomerase 1 inhibitors used in preclinical development (green). C Next-generation topoisomerase I inhibitors as potential payloads for ADCs. Notations within the figure: [ADC name], antibody, payload

Fig. 3

Structure of antibody–drug conjugates that have reach clinical trials and their payloads (blue) classified regarding their mechanism of action. Notations within the figure: [ADC name], antibody, payload

Fig. 4

Chemical structure of unconventional ADC payloads conjugated at the preclinical stage

Fig. 5

Schematic representation of the ADC payload’s target landscape beyond microtubules and DNA-intercalating agents. Notations: FDA-approved ADCs, ADCs in clinical trials