Pharmacodynamic and Antineoplastic Activity of BI 836845, a Fully Human IGF Ligand-Neutralizing Antibody, and Mechanistic Rationale for Combination with Rapamycin
Pharmacodynamic and Antineoplastic Activity of BI 836845, a Fully Human IGF Ligand-Neutralizing Antibody, and Mechanistic Rationale for Combination with Rapamycin
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DOI：
10.1158/1535-7163.mct-13-0598
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发表时间：
2014-02-01
影响因子：
5.7
通讯作者：
Adam, Paul J.
中科院分区：
文献类型：
--
作者：
Friedbichler, Katrin;Hofmann, Marco H.;Adam, Paul J.
胰岛素样生长因子（IGF）信号被认为在多种癌症类型的发展和进展中发挥作用。迄今为止，旨在破坏IGF信号传导的治疗策略主要集中在靶向IGF-I受体（IGF-IR）的抗体上。在此，我们描述了BI 836845的药理学特征，BI 836845是一种全人源单克隆抗体，通过选择性中和IGF配体的生物活性，利用替代方法抑制IGF信号传导。BI 836845的生化分析证明其对人IGF-I和IGF-II具有高亲和力，可有效抑制IGF诱导的体外IGF-IR和IR-A活化。与啮齿动物IGF的交叉反应性使得能够在临床前模型中严格评估BI 836845的药理学活性。大鼠药效学研究显示，在无代谢不良反应的情况下，血清IGF生物活性显著降低，导致生长抑制，表现为体重增加和尾长减少。此外，BI 836845通过阻断体外以及裸鼠人肿瘤异种移植模型中雷帕霉素诱导的上游信号传导增加，降低了源自不同癌症类型的人细胞系的增殖，并增强了雷帕霉素的抗肿瘤疗效。我们的数据表明，与直接靶向IGF-I受体的药物相比，BI 836845代表了一种可能更有效和更耐受的IGF信号传导抑制方法，在临床研究中可能与其他靶向药物合理联合。Mol Cancer Ther; 13（2）; 399-409. (C)2013年AACR。
Insulin-like growth factor (IGF) signaling is thought to play a role in the development and progression of multiple cancer types. To date, therapeutic strategies aimed at disrupting IGF signaling have largely focused on antibodies that target the IGF-I receptor (IGF-IR). Here, we describe the pharmacologic profile of BI 836845, a fully human monoclonal antibody that utilizes an alternative approach to IGF signaling inhibition by selectively neutralizing the bioactivity of IGF ligands. Biochemical analyses of BI 836845 demonstrated high affinity tohuman IGF-I and IGF-II, resulting in effective inhibition of IGF-induced activation of both IGF-IR and IR-A in vitro. Cross-reactivity to rodent IGFs has enabled rigorous assessment of the pharmacologic activity of BI 836845 in preclinical models. Pharmacodynamic studies in rats showed potent reduction of serum IGF bioactivity in the absence of metabolic adverse effects, leading to growth inhibition as evidenced by reduced body weight gain and tail length. Moreover, BI 836845 reduced the proliferation of human cell lines derived from different cancer types and enhanced the antitumor efficacy of rapamycin by blocking a rapamycin-induced increase in upstream signaling in vitro as well as in human tumor xenograft models in nude mice. Our data suggest that BI 836845 represents a potentially more effective and tolerable approach to the inhibition of IGF signaling compared with agents that target the IGF-I receptor directly, with potential for rational combinations with other targeted agents in clinical studies. Mol Cancer Ther; 13(2); 399-409. (C) 2013 AACR.