Synthetic Lethality Exploitation by an Anti–Trop-2-SN-38 Antibody–Drug Conjugate, IMMU-132, Plus PARP Inhibitors in BRCA1/2–wild-type Triple-Negative Breast Cancer

Abstract

Purpose: Both PARP inhibitors (PARPi) and sacituzumab govitecan are currently under clinical evaluation in triple-negative breast cancer (TNBC). We sought to investigate the combined DNA-damaging effects of the topoisomerase I (Topo I)-inhibitory activity of IMMU-132 with PARPi disruption of DNA repair in TNBC.Experimental Design: In vitro, human TNBC cell lines were incubated with IMMU-132 and various PARPi (olaparib, rucaparib, or talazoparib) to determine the effect on growth, doublestranded DNA (dsDNA) breaks, and cell-cycle arrest. Mice bearing BRCA1/2-mutated or -wild-type human TNBC tumor xenografts were treated with the combination of IMMU-132 and PARPi (olaparib or talazoparib). Study survival endpoint was tumor progression to >1.0 cm 3 and tolerability assessed by hematologic changes.Results: Combining IMMU-132 in TNBC with all three different PARPi results in synergistic growth inhibition, increased dsDNA breaks, and accumulation of cells in the Sphase of the cell cycle, regardless of BRCA1/2 status. A combination of IMMU-132 plus olaparib or talazoparib produces significantly improved antitumor effects and delay in time-totumor progression compared with monotherapy in mice bearing BRCA1/2-mutated HCC1806 TNBC tumors. Furthermore, in mice bearing BRCA1/2-wild-type tumors (MDA-MB-468 or MDA-MB-231), the combination of IMMU-132 plus olaparib imparts a significant antitumor effect and survival benefit above that achieved with monotherapy. Most importantly, this combination was well tolerated, with no substantial changes in hematologic parameters.Conclusions: These data demonstrate the added benefit of combining Topo I inhibition mediated by IMMU-132 with synthetic lethality provided by PARPi in TNBC, regardless of BRCA1/2 status, thus supporting the rationale for such a combination clinically. Clin Cancer Res; 23(13); 3405-15. Ó2017 AACR.

Sacituzumab govitecan (IMMU‐132), an anti‐Trop‐2‐SN‐38 antibody‐drug conjugate for the treatment of diverse epithelial cancers: Safety and pharmacokinetics

“…In addition, combination therapy trials with select agents are being developed based on promising preclinical results. 36…”

IMMU-140, a Novel SN-38 Antibody–Drug Conjugate Targeting HLA-DR, Mediates Dual Cytotoxic Effects in Hematologic Cancers and Malignant Melanoma

“…In particular, IMMU-114 was shown to mediate an increase in phosphorylation of ERK1/2, JNK, and p38 in response to the increase in ROS (8). Conversely, SN-38, as a topoisomerase I (topo-I) inhibitor, impedes DNA replication, resulting in triggering of the intrinsic apoptosis pathway that leads to activation of the caspase-cleavage cascade, PARP cleavage, and ultimately to dsDNA breaks and cell death (18)(19)(20). Given these two different effects mediated by binding to HLA-DR and SN-38 delivery, IMMU-140 was predicted to have nonoverlapping, dual-signaling effects on targeted neoplastic cells.…”

“…Western blot assessment of ERK1/2 phosphorylation, PARP cleavage, and double-stranded DNA breaks in vitro Evaluation of ERK1/2 phosphorylation, PARP cleavage, and dsDNA breaks has previously been described (8,(18)(19)(20) and presented in Supplementary Data. IMMU-140 and IMMU-114 concentrations and incubation times are indicated in the figures or figure legends.…”

“…Cytotoxicity imparted by SN-38 is through impaired DNA replication resulting in activation of the caspase cascade, ultimately leading to the cleavage of PARP and double-stranded DNA (dsDNA) breaks (18)(19)(20). Accordingly, two different mechanisms of action leading to cell death can be triggered by HLA-DR-targeting of IMMU-140.…”

“…Other ADCs utilizing SN-38 (sacituzumab govitecan and labetuzumab govitecan) being studied in solid tumors have been well tolerated, having clinically significant objective responses in patients given multiple cycles over >6 months, and with manageable neutropenia being the major toxicity (13)(14)(15)(16)(17). Cytotoxicity mediated by SN-38 is through DNA breakage triggering the intrinsic apoptotic pathway, resulting in activation of the caspase cascade, PARP cleavage, and further DNA degradation (18)(19)(20). Thus, our goal was to determine if SN-38, the active metabolite of a drug (irinotecan) not commonly used in hematopoietic cancers, would prove to be an effective and safe therapeutic when targeted with the anti-HLA-DR antibody, IMMU-114.…”