Differences in promiscuity for antibody-FcRn interactions across species: implications for therapeutic antibodies
Differences in promiscuity for antibody-FcRn interactions across species: implications for therapeutic antibodies
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DOI：
10.1093/intimm/13.12.1551
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发表时间：
2001-12-01
影响因子：
4.4
通讯作者：
Ward, ES
中科院分区：
文献类型：
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作者：
Ober, RJ;Radu, CG;Ward, ES
治疗性抗体的临床前试验经常在小鼠中进行以评估药代动力学和功效。然而，小鼠IgG从人体循环中快速清除的观察结果表明，小鼠可能并不总是理想的模型。Fc受体FcRn调节小鼠中IgG的血清半衰期，并且很可能在人体中具有类似的功能。在当前的研究中，我们已经使用表面等离子体共振对人或小鼠形式的FcRn与来自各种物种的IgG的相互作用进行了广泛的分析。我们表明，与小鼠FcRn相反，人FcRn在其对来自不同物种的IgG的结合特异性方面令人惊讶地严格。人FcRn与人、兔和豚鼠IgG结合，但与大鼠、牛、绵羊或小鼠IgG结合不显著（与小鼠IgG2b弱结合除外）。相比之下，小鼠FcRn与分析的所有IgG结合。已使用经工程改造以在细胞表面表达人FcRn的转染子证实人FcRn与小鼠IgG 1缺乏结合。我们的研究结果提供了一个神秘的观察，小鼠IgG在人类中的行为有害的分子解释。这些研究对治疗性抗体的成功应用具有意义。
Preclinical tests of therapeutic antibodies are frequently carried out in mice to evaluate pharmacokinetics and efficacy. However, the observation that mouse IgG are cleared rapidly from the human circulation suggests that mice may not always be an ideal model. The Fc receptor, FcRn, regulates the serum half-lives of IgG in mice and most likely has a similar function in humans. In the current study we have carried out an extensive analysis of the interaction of the human or mouse forms of FcRn with IgG from various species using surface plasmon resonance. We show that in contrast to mouse FcRn, human FcRn is surprisingly stringent in its binding specificity for IgG derived from different species. Human FcRn binds to human, rabbit and guinea pig IgG, but not significantly to rat, bovine, sheep or mouse IgG (with the exception of weak binding to mouse IgG2b). In contrast, mouse FcRn binds to all IgG analyzed. The lack of binding of human FcRn to mouse IgG1 has been confirmed using transfectants that have been engineered to express human FcRn on the cell surface. Our results provide a molecular explanation for the enigmatic observation that mouse IgG behave anomalously in humans. These studies have implications for the successful application of therapeutic antibodies.