New Life of Topoisomerase I Inhibitors as Antibody-Drug Conjugate Warheads

Abstract

Antibody-drug conjugates (ADC) allow the delivery of cytotoxic chemotherapeutic agents to tumors. Two ADC delivering topoisomerase I (TOP1) poisons (Enhertu and Trodelvy) have recently been FDA-approved for Her2- and Trop2-expressing solid tumors. In a recent study, a TOP1-anti B7-H4 ADC was described and shown to be synergistic with a novel PARP1-selective inhibitor. See related article by Kinneer et al., p. 1086.

Figure 1.

Key parameters to be considered for optimizing TOP1cc-targeted ADCs. 1) The ADC needs to be stable in blood and to not release the payload before it reaches its cancer cell targets. 2) The epitope has to be expressed on cancer but not in normal cells as determined by histology and pathology methods and/or RNA seq. The inset shows the expression of VTCN1 (which encodes B7-H4) in the 1,019 cancer cell lines of the Broad-MIT (snapshot from https://discover.nci.nih.gov) (note that multiple breast and ovarian cell lines co-express VTCN1 and ERBB2 (which encodes Her2). 3) The ADC needs to be readily internalized into the cancer cells. 4) The payload should be released readily inside the cytosol of the cancer cells. 5) If the payload is known to be substrate for the drug efflux ABC transporter(s), expression of the relevant ABC transporters determined as tumor overexpressing such transporter may not respond to the ADC. 6) Target engagement (i.e., trapping of TOP1 cleavage complexes) can be measured by induction of γH2AX and TOP1 degradation. 7) Determinants of response such as homologous recombination deficiency (HRD) and Schlafen 11 (SLFN11) can be assessed to predict response and potentially select patients. 8) Combination with DNA damage response (DDR) inhibitors such as the PARP1 inhibitor AZD5305 or ATR inhibitors should synergize with the TOP1 inhibitor only in the cancer cells while sparing normal cells. 9) release of the payload from the dead tumor cells and by the release of the payload in the extracellular milieu can attack neighboring cells with low expression of the surface target epitope.