Abstract 2651: Impressive efficacy and safety profile of a novel generation duocarmycin-based HER2-targeting ADC
Authors: Dokter Willem , Ubink Ruud , Lee Miranda van der , Vleuten Monique van der , Achterberg Tanja van , Jacobs Daniëlle , Dobbelsteen Diels van den , Egging David , Mattaar Ellen , Groothuis Patrick , Beusker Patrick , Coumans Ruud , Elgersma Ronald , Eppink Michel , Roo Guy de , Verheijden Gijs , Timmers Marco 
Published: May 2015

Abstract
We have built a linker-drug platform based on a cleavable linker-duocarmycin payload for the development of novel generation antibody-drug conjugates. SYD983, a lead ADC originating from that platform, is a cysteine-coupled HER2-targeting ADC based on trastuzumab. SYD983 is a heterogeneous product that consists of a mixture of naked Ab and ADCs with a drug-to-antibody ratio (DAR) of 2, 4, 6, the mean DAR being 2.0.
We have shown that SYD983 binds to HER2, induces antibody-dependent cell-mediated cytotoxicity, and is efficiently internalized into HER2-expressing cells. SYD983 very potently kills HER2-expressing cells in vitro and is inactive in cells that don't express HER2. SYD983 is stable in human and cynomolgus monkey (CM) plasma in vitro but has relatively poor stability in mouse plasma. The latter is due to mouse-specific carboxylesterase (CES1c) since stability of SYD983 in plasma of CES1c knockout mice is similar to that in human and CM plasma. SYD983 could be dosed up to 30 mg/kg in CM in vivo with high exposure and stable kinetics and without severe toxic effects. The CM safety study showed no SYD983-induced thrombocytopenia and no induction of peripheral sensory neuropathy, which both commonly occur in studies with ADCs based on tubulin inhibitors. Finally, to reduce heterogeneity we have further fractionated SYD983 by hydrophobic interaction chromatography resulting in an ADC predominantly containing DAR2 and DAR4 species and we designated the resulting purified and more homogeneous ADC as SYD985. In line with its increased average DAR and the absence of naked Ab, SYD985 (average DAR of 2.7) shows increased potency in vitro compared to SYD983. In vivo, SYD985 showed high anti-tumor activity in two patient-derived xenograft models of HER2 positive metastatic breast cancers which underscores the potential for SYD985 in this indication. We have further initiated a program to directly compare SYD985 to T-DM1 for anti-tumor activity in a series of tumors with different HER2 status of which the results are published in a separate accompanying abstract.
In conclusion, the data obtained indicates great potential for SYD985 to become an effective drug for patients with HER2-positive cancers. Clinical studies will further elucidate how the characteristics revealed in the preclinical studies, will translate into a benefit for patients. Taken more generally, we conclude that this novel generation duocarmycin-based LD technology could be used on other mAbs to create effective and safe ADCs to treat different forms of cancer.
Citation Format: Willem Dokter, Ruud Ubink, Miranda van der Lee, Monique van der Vleuten, Tanja van Achterberg, Daniëlle Jacobs, Diels van den Dobbelsteen, David Egging, Ellen Mattaar, Patrick Groothuis, Patrick Beusker, Ruud Coumans, Ronald Elgersma, Michel Eppink, Guy de Roo, Gijs Verheijden, Marco Timmers. Impressive efficacy and safety profile of a novel generation duocarmycin-based HER2-targeting ADC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2651. doi:10.1158/1538-7445.AM2014-2651