Oncotarget

Research Papers:

Anetumab ravtansine inhibits tumor growth and shows additive effect in combination with targeted agents and chemotherapy in mesothelin-expressing human ovarian cancer models

Maria Quanz, Urs B. Hagemann, Sabine Zitzmann-Kolbe, Beatrix Stelte-Ludwig, Sven Golfier, Cem Elbi, Dominik Mumberg, Karl Ziegelbauer and Christoph A. Schatz _

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Oncotarget. 2018; 9:34103-34121. https://doi.org/10.18632/oncotarget.26135

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Abstract

Maria Quanz1, Urs B. Hagemann1, Sabine Zitzmann-Kolbe1, Beatrix Stelte-Ludwig2, Sven Golfier1, Cem Elbi3, Dominik Mumberg1, Karl Ziegelbauer1 and Christoph A. Schatz1

1Bayer AG Preclinical Research, Pharmaceuticals, Berlin 13353, Germany

2Bayer AG Preclinical Research, Pharmaceuticals, Wuppertal 42096, Germany

3Bayer US LLS, Whippany, NJ 07981, USA

Correspondence to:

Christoph A. Schatz, email: christoph.schatz@bayer.com

Keywords: mesothelin; anetumab ravtansine; antibody-drug conjugate; copanlisib; ovarian cancer

Received: January 19, 2018     Accepted: September 01, 2018     Published: September 25, 2018

ABSTRACT

Despite the recent advances in the treatment of ovarian cancer, it remains an area of high unmet medical need. Epithelial ovarian cancer is associated with high levels of mesothelin expression, and therefore, mesothelin is an attractive candidate target for the treatment of this disease. Herein, we investigated the antitumor efficacy of the mesothelin-targeting antibody-drug conjugate (ADC) anetumab ravtansine as a novel treatment option for ovarian cancer in monotherapy and in combination with the antitumor agents pegylated liposomal doxorubicin (PLD), carboplatin, copanlisib and bevacizumab. Anetumab ravtansine showed potent antitumor activity as a monotherapy in ovarian cancer models with high mesothelin expression. No activity was seen in mesothelin-negative models. The combination of anetumab ravtansine with PLD showed additive anti-proliferative activity in vitro, which translated into improved therapeutic in vivo efficacy in ovarian cancer cell line- and patient-derived xenograft (PDX) models compared to either agents as a monotherapy. The combination of anetumab ravtansine with the PI3Kα/δ inhibitor copanlisib was additive in the OVCAR-3 and OVCAR-8 cell lines in vitro, showing increased apoptosis in response to the combination treatment. In vivo, the combination of anetumab ravtansine with copanlisib resulted in more potent antitumor activity than either of the treatments alone. Likewise, the combination of anetumab ravtansine with carboplatin or bevacizumab showed improved in vivo efficacy in the ST081 and OVCAR-3 models, respectively. All combinations were well-tolerated. Taken together, these data support the development of anetumab ravtansine for ovarian cancer treatment and highlight its suitability for combination therapy with PLD, carboplatin, copanlisib, or bevacizumab.


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