Anetumab ravtansine: a novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect.

Abstract

Mesothelin is a tumor differentiation antigen frequently overexpressed in tumors such as mesothelioma, ovarian, pancreatic, and lung adenocarcinomas while showing limited expression in nonmalignant tissues. Mesothelin is therefore an attractive target for cancer therapy using antibody-drug conjugates (ADC). This study describes the detailed characterization of anetumab ravtansine, here referred to as BAY 94-9343, a novel ADC consisting of a human anti-mesothelin antibody conjugated to the maytansinoid tubulin inhibitor DM4 via a disulfide-containing linker. Binding properties of the anti-mesothelin antibody were analyzed using surface plasmon resonance, immunohistochemistry, flow cytometry, and fluorescence microscopy. Effects of BAY 94-9343 on cell proliferation were first studied in vitro and subsequently in vivo using subcutaneous, orthotopic, and patient-derived xenograft tumor models. The antibody binds to human mesothelin with high affinity and selectivity, thereby inducing efficient antigen internalization. In vitro, BAY 94-9343 demonstrated potent and selective cytotoxicity of mesothelin-expressing cells with an IC(50) of 0.72 nmol/L, without affecting mesothelin-negative or nonproliferating cells. In vivo, BAY 94-9343 localized specifically to mesothelin-positive tumors and inhibited tumor growth in both subcutaneous and orthotopic xenograft models. In addition, BAY 94-9343 was able to induce a bystander effect on neighboring mesothelin-negative tumor cells. Antitumor efficacy of BAY 94-9343 correlated with the amount of mesothelin expressed and was generally superior to that of standard-of-care regimen resulting in complete tumor eradication in most of the models. BAY 94-9343 is a selective and highly potent ADC, and our data support its development for the treatment of patients with mesothelin-expressing tumors.

• Authors: Sven Golfier, Charlotte Kopitz, Antje Kahnert, Iring Heisler, Christoph A Schatz, Beatrix Stelte-Ludwig, Anke Mayer-Bartschmid, Kerstin Unterschemmann, Sandra Bruder, Lars Linden, Axel Harrenga, Peter Hauff, Frank-Detlef Scholle, Beate Müller-Tiemann, Bertolt Kreft, Karl Ziegelbauer
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 13 Issue 6 Pg. 1537-48 (Jun 2014) ISSN: 1538-8514 [Electronic] United States
• PMID: 24714131 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal
• GPI-Linked Proteins
• Immunoconjugates
• Maytansine
• Mesothelin
• anetumab ravtansine

Topics

• Antibodies, Monoclonal (administration & dosage, immunology)
• Antibody-Dependent Cell Cytotoxicity (immunology)
• Bystander Effect
• Cell Line, Tumor
• GPI-Linked Proteins (antagonists & inhibitors, immunology)
• Gene Expression Regulation, Neoplastic (immunology)
• Humans
• Immunoconjugates (administration & dosage)
• Maytansine (administration & dosage, analogs & derivatives)
• Mesothelin
• Molecular Targeted Therapy
• Neoplasms (drug therapy, immunology, pathology)
• Xenograft Model Antitumor Assays