Abstract C025: HexaBody-DR5/DR5 (GEN1029) shows potent preclinical antitumor activity in a variety of patient-derived xenograft (PDX) tumor models

Background: Hyperclustering of death receptor 5 (DR5) and subsequent induction of apoptosis, which normally occurs upon binding of its ligand TRAIL, can be mimicked by agonistic antibodies (Abs). However, clinical efficacy of conventional DR5 Abs has been disappointing. To improve antibody-mediated DR5 clustering on cancer cells, we utilized the HexaBody® antibody technology. This antibody platform is based on the discovery that IgG molecules can organize into hexamers through intermolecular Fc-Fc interactions upon binding to membrane-bound targets. HexaBody molecules are IgG1 Abs with a single point mutation in the Fc domain that enhances hexamerization. HexaBody-DR5/DR5 is a 1:1 mixture of two non-competing anti-DR5 HexaBody molecules that induces potent caspase-dependent apoptosis through hexamer-dependent hyperclustering of DR5 on the cell surface. We previously showed that HexaBody-DR5/DR5 induced superior potency compared to conventional DR5 antibodies in vitro and in vivo. Methods: To obtain preclinical proof-of-concept for targeting specific solid tumors using HexaBody-DR5/DR5, we performed a patient-derived xenograft (PDX) mouse clinical trial (1 mouse per group design) using a large number of colorectal (CRC) (100), gastric (19), urothelial (13), non-small cell lung cancer (NSCLC) (90), and triple-negative breast cancer (TNBC) (20) PDX models. Results: HexaBody-DR5/DR5 showed potent anti-tumor activity (tumor stasis or tumor regression) in a substantial proportion of the CRC (36%), gastric (42%) and urothelial (54%) models. Additional in vivo studies comparing single vs multiple dosing demonstrated that maximal anti-tumor activity was already achieved after a single dose of HexaBody-DR5/DR5. A Phase 1/2 clinical trial to determine the RP2D and assess clinical safety of HexaBody-DR5/DR5 in cancer patients is currently ongoing (NCT03576131), from which a case study will be presented. Conclusions: Potent anti-tumor activity of HexaBody-DR5/DR5 was observed in large and diverse panels of CRC, gastric and urothelial PDX models, providing preclinical rationale for the clinical evaluation of HexaBody-DR5/DR5 in these indications. Citation Format: Marije B Overdijk, Michael Cecchini, Kristin Strumane, Marcel Brandhorst, Andreas Lingnau, Paul W.H.I. Parren, Merete Ellekilde-Pedersen, Ulf Forssmann, Tahamtan Ahmadi, A. Kate Sasser, Janine Schuurman, Esther C.W. Breij, Patricia LoRusso. HexaBody-DR5/DR5 (GEN1029) shows potent preclinical antitumor activity in a variety of patient-derived xenograft (PDX) tumor models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C025. doi:10.1158/1535-7163.TARG-19-C025