Abstract 744: ADCT-701, a novel pyrrolobenzodiazepine (PBD) dimer-based antibody-drug conjugate (ADC) targeting DLK1-expressing tumors
Authors: Zammarchi Francesca , Havenith Karin , Chivers Simon , Hogg Paul W. , Britten Charlie , Dissanayake Sandamali , Tyrer Peter , Bertelli Francois , Hutchinson Ian , Masterson Luke , Howard Phil , Hartley John A. , Berkel Patrick H. van 
Published: August 2018

Abstract
Delta-like 1 homolog protein (DLK-1) is an EGF-like membrane bound protein consisting of six tandem EGF-like repeats, a juxtamembrane region with a TACE (ADAM17)-mediated cleavage site, a transmembrane domain, and a short intracellular tail. DLK-1 is strongly expressed during fetal development, while its expression is highly restricted in adults. Conversely, DLK-1 gets re-expressed in several tumors, such as neuroblastoma, hepatocellular carcinoma (HCC), rhabdomyosarcoma, small cell lung cancer, myelodysplastic syndrome and acute myeloid leukemia. Interestingly, in HCC DLK-1 has been shown to be a marker of cancer stem cells, a subpopulation of cells responsible for tumor initiation, growth, metastasis, and recurrence. Altogether, DLK-1 represents an attractive target for an antibody-drug conjugate (ADC) approach based on its selective expression in a wide range of malignancies and restricted expression in healthy organs, as well as its expression on HCC cancer stem cells. ADCT-701 is an ADC composed of a humanized IgG1 antibody against human DLK-1, site-specifically conjugated using GlycoconnectTM technology to PL1601, which contains a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199. The purpose of this study was to characterize the in vitro and in vivo anti-tumor activity of ADCT-701 in human cancer cell lines and patient-derived xenograft (PDX) models and to determine its safety and tolerability in the rat. In vitro, ADCT-701 demonstrated potent cytotoxicity in a panel of human cancer cell lines of different origin and levels of DLK-1, while its potency was strongly reduced in DLK-1-negative cell lines. In vivo, ADCT-701 showed potent anti-tumor activity in the DLK1-expressing neuroblastoma-derived SK-N-FI xenograft in which a single dose of ADCT-701 at 0.5 or 1 mg/kg showed dose-dependent anti-tumor activity compared to the vehicle- and isotype control ADC-treated mice. At 1 mg/kg, ADCT-701 resulted in 1/9 partial responders (PR) and 4/9 complete responder (CR), one of which was tumor-frees survivors (TFS) at the end of the study on day 60. Moreover, ADCT-701 showed dose-dependent anti-tumor activity in a HCC PDX model when tested as a single dose at 0.1, 0.3 or 1 mg/kg. At the highest dose tested, ADCT-701 resulted in 3/8 PR and 2/8 CR, while none of the mice treated with the vehicle or the isotype-control ADC (1 mg/kg, single dose) showed any activity. ADCT-701 was stable, well tolerated and showed a favorable pharmacokinetic profile in the rat with a half-life of 9 days and a maximum tolerated dose of at least 5 mg/kg. In conclusion, ADCT-701 demonstrated potent and specific in vitro and in vivo anti-tumor activity in DLK-1-expressing cancer-derived models and it was stable and well tolerated in the rat, warranting further development of this ADC into the clinic.
Citation Format: Francesca Zammarchi, Karin Havenith, Simon Chivers, Paul W. Hogg, Charlie Britten, Sandamali Dissanayake, Peter Tyrer, Francois Bertelli, Ian Hutchinson, Luke Masterson, Phil Howard, John A. Hartley, Patrick H. van Berkel. ADCT-701, a novel pyrrolobenzodiazepine (PBD) dimer-based antibody-drug conjugate (ADC) targeting DLK1-expressing tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 744.