Quantification of Binding of IGF-1 to BI 836845, a Candidate Therapeutic Antibody Against IGF-1 and IGF-2, and Effects of This Antibody on IGF-1:IGFBP-3 Complexes In Vitro and in Male C57BL/6 Mice
Quantification of Binding of IGF-1 to BI 836845, a Candidate Therapeutic Antibody Against IGF-1 and IGF-2, and Effects of This Antibody on IGF-1:IGFBP-3 Complexes In Vitro and in Male C57BL/6 Mice
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DOI：
10.1210/en.2013-1791
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发表时间：
2014-03-01
期刊：
影响因子：
4.8
通讯作者：
Pollak, Michael
中科院分区：
文献类型：
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作者：
Mireuta, Matei;Birman, Elena;Pollak, Michael
IGF-1和IGF-2是通过IGF-1受体(IGF-1R)作用的有丝分裂原。IGF系统在肿瘤形成中的重要性已经在几个模型中得到证实，IGF-1信号已成为药物开发的靶点。候选药物BI 836845是一种完全人类免疫球蛋白1配体中和抗体，与胰岛素样生长因子-1和胰岛素样生长因子-2发生交叉反应。在临床前研究中，它已被证明可以减少IGF-1R的磷酸化和细胞增殖。在啮齿动物研究中，服用BI 836845会导致血清中总的胰岛素样生长因子-1浓度大幅增加，尽管通过激酶激活试验测定血清中胰岛素样生长因子-1的活性降低。尽管抗胰岛素样生长因子配体抗体已经进入临床试验，但它们对胰岛素样生长因子结合蛋白的影响还没有被描述。在这份报告中，我们开发了一种新的技术来测量配体-BI 836845结合，并将其应用于不同环境下的小鼠模型。我们发现，虽然观察到血清总胰岛素样生长因子-1水平的大幅增加，但绝大多数配体以BI-836845的复合体形式存在，并且总血清胰岛素样生长因子结合蛋白-3水平降低。最后，我们发现BI 836845治疗导致生长激素水平的增加，这一发现与试图在脑下垂体水平代偿的发现一致。我们的结果揭示了BI 836845给药的生理后遗症的复杂性，这对确定最佳给药方案和开发临床试验的药效终点具有重要意义。
IGF-1 and IGF-2 are potent mitogens acting through the IGF-1 receptor (IGF-1R). The importance of the IGF system in neoplasia has been demonstrated in several models, and IGF-1 signaling has become a target for drug development. The drug candidate BI 836845 is a fully human IgG1 ligand-neutralizing antibody that cross-reacts with IGF-1 and IGF-2. It has been shown to reduce both IGF-1R phosphorylation and cellular proliferation in preclinical studies. In rodent studies, administration of BI 836845 leads to large increases in total IGF-1 concentration in serum, despite reduced serum IGF-1 activity as measured by a kinase activation assay. Despite the fact that anti-IGF- ligand antibodies have entered clinical trials, their effect on IGF-binding proteins has not been described. In this report, we developed a novel technique to measure ligand-BI 836845 binding, and we apply it to a mouse model in various contexts. We show that although large increases in total serum IGF-1 levels are observed, the vast majority of ligand is present as a complex with BI 836845, and total serum IGF-binding protein-3 levels are decreased. Finally, we show that BI 836845 treatment induces an increase in GH levels, a finding consistent with attempted compensation at the level of the pituitary. Our results reveal complexities in the physiologic sequelae of BI 836845 administration that have implications for determination of optimal dosing regimens and for development of pharmacodynamic endpoints for clinical trials.