Abstract 1780: Anetumab ravtansine has single-agent activity in mesothelin-expressing human ovarian cancer models and potentiates the activity of chemotherapeutics and targeted agents
Authors: Schatz Christoph A. , Quanz Maria , Hagemann Urs B. , Zitzmann-Kolbe Sabine , Stelte-Ludwig Beatrix , Golfier Sven , Kopitz Charlotte , Elbi Cem , Ziegelbauer Karl , Mumberg Dominik 
Published: August 2018

Abstract
Ovarian cancer remains an area of high unmet medical need, with 239,000 patients newly diagnosed per year. Here we describe the mesothelin-targeting antibody drug-conjugate anetumab ravtansine as a novel treatment option for ovarian cancer. Internalization of anetumab ravtansine and co-localization with lysosomal markers in ovarian cancer cells was accompanied by rapid resynthesis of mesothelin, which may allow consecutive anetumab ravtansine treatment cycles. The strong antitumor activity of anetumab ravtansine was preserved during repeated treatment cycles in the OVCAR-3 ovarian cancer in vivo model. Mechanistically, treatment with anetumab ravtansine caused mitotic arrest characterized by increased pHH3 signal and monopolar spindle structures. Interestingly, anetumab ravtansine monotherapy also induced DNA damage as indicated by focal γH2AX signals. Ultimately, the cells engaged in apoptotic cell death. Strong in vitro monotherapy activity was demonstrated in a set of 11 ovarian cancer cell lines with IC50s between 3 and 90nM. The in vivo efficacy of anetumab ravtansine dosed at 2.5 mg/kg Q3Dx3 i.v. anetumab ravtansine was evaluated in 9 human ovarian cancer models with varying mesothelin expression levels. Strong in vivo efficacy at this moderate dose with T/C &lt;0.2 was seen in OVCAR-3 cell line and the PDX model OvCa6668. Efficacy was generally higher in tumors with strong mesothelin expression. No activity was seen in mesothelin-negative ovarian cancer models. Combination with the PI3K inhibitor copanlisib was additive in the OVCAR-3 and OVCAR-8 cell line in vitro, showing increased apoptosis in the combination treatment. In vivo, anetumab ravtansine + copanlisib in OVCAR-3 tumors consistently resulted in greater efficacy than with either treatment alone. Both single treatments and the combination were well tolerated. Combination of anetumab ravtansine with bevacizumab, the only antibody therapy approved for ovarian cancer to date, also showed increased in vivo efficacy in the combination while being well tolerated. Next combination with PEGylated doxorubicin (PLD) was investigated. The combination of anetumab ravtansine plus PLD in OVCAR-8 cells showed additive effects and in vivo in OVCAR-8 tumors, the combination consistently showed better therapeutic efficacy than either therapy alone. Overall, these data support the development of anetumab ravtansine in ovarian cancer and suggest combinations with copanlisib, bevacizumab or PLD.
Citation Format: Christoph A. Schatz, Maria Quanz, Urs B. Hagemann, Sabine Zitzmann-Kolbe, Beatrix Stelte-Ludwig, Sven Golfier, Charlotte Kopitz, Cem Elbi, Karl Ziegelbauer, Dominik Mumberg. Anetumab ravtansine has single-agent activity in mesothelin-expressing human ovarian cancer models and potentiates the activity of chemotherapeutics and targeted agents [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 1780.