Anetumab Ravtansine: A Novel Mesothelin-Targeting Antibody-Drug Conjugate Cures Tumors with Heterogeneous Target Expression Favored by Bystander Effect
Anetumab Ravtansine: A Novel Mesothelin-Targeting Antibody-Drug Conjugate Cures Tumors with Heterogeneous Target Expression Favored by Bystander Effect
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DOI：
10.1158/1535-7163.mct-13-0926
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发表时间：
2014-06-01
影响因子：
5.7
通讯作者：
Ziegelbauer, Karl
中科院分区：
文献类型：
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作者：
Golfier, Sven;Kopitz, Charlotte;Ziegelbauer, Karl
间皮素是一种肿瘤分化抗原，经常在肿瘤如间皮瘤、卵巢癌、胰腺癌和肺腺癌中过表达，而在非恶性组织中表达有限。因此，间皮素是使用抗体-药物缀合物（ADC）的癌症治疗的有吸引力的靶标。本研究描述了anetumab ravtansine（此处称为BAY 94-9343）的详细表征，这是一种新型ADC，由人抗间皮素抗体通过含二硫化物的接头与美登木素微管蛋白抑制剂DM 4偶联组成。使用表面等离子体共振、免疫组织化学、流式细胞术和荧光显微术分析抗间皮素抗体的结合特性。BAY 94-9343对细胞增殖的影响首先在体外研究，随后使用皮下、原位和患者来源的异种移植肿瘤模型在体内研究。该抗体以高亲和力和选择性结合人间皮素，从而诱导有效的抗原内化。在体外，BAY 94-9343表现出对间皮素表达细胞的强效和选择性细胞毒性，IC 50为0.72 nmol/L，而不影响间皮素阴性或非增殖细胞。在体内，BAY 94 -9343特异性定位于间皮素阳性肿瘤，并抑制皮下和原位异种移植模型中的肿瘤生长。此外，BAY 94-9343能够诱导对相邻间皮素阴性肿瘤细胞的旁观者效应。BAY 94-9343的抗肿瘤功效与间皮素表达的量相关，并且通常上级于标准护理方案，导致在大多数模型中完全肿瘤根除。BAY 94-9343是一种选择性和高效的ADC，我们的数据支持其用于治疗表达间皮素的肿瘤患者。(C)2014年AACR。
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 IC50 of 0.72 nmol/L, without affecting mesothelin-negative or nonproliferating cells. In vivo, BAY94-9343 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. (C) 2014 AACR.