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首页> 美国卫生研究院文献>The Journal of Biological Chemistry >Immunoglobulin domain interface exchange as a platform technology for the generation of Fc heterodimers and bispecific antibodies
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Immunoglobulin domain interface exchange as a platform technology for the generation of Fc heterodimers and bispecific antibodies

机译：免疫球蛋白结构域界面交换作为产生Fc异二聚体和双特异性抗体的平台技术

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摘要

Bispecific antibodies (bsAbs) are of significant importance to the development of novel antibody-based therapies, and heavy chain (Hc) heterodimers represent a major class of bispecific drug candidates. Current technologies for the generation of Hc heterodimers are suboptimal and often suffer from contamination by homodimers posing purification challenges. Here, we introduce a new technology based on biomimicry wherein the protein-protein interfaces of two different immunoglobulin (Ig) constant domain pairs are exchanged in part or fully to design new heterodimeric domains. The method can be applied across Igs to design Fc heterodimers and bsAbs. We investigated interfaces from human IgA CH3, IgD CH3, IgG1 CH3, IgM CH4, T-cell receptor (TCR) α/β, and TCR γ/δ constant domain pairs, and we found that they successfully drive human IgG1 CH3 or IgM CH4 heterodimerization to levels similar to or above those of reference methods. A comprehensive interface exchange between the TCR α/β constant domain pair and the IgG1 CH3 homodimer was evidenced by X-ray crystallography and used to engineer examples of bsAbs for cancer therapy. Parental antibody pairs were rapidly reformatted into scalable bsAbs that were free of homodimer traces by combining interface exchange, asymmetric Protein A binding, and the scFv × Fab format. In summary, we successfully built several new CH3- or CH4-based heterodimers that may prove useful for designing new bsAb-based therapeutics, and we anticipate that our approach could be broadly implemented across the Ig constant domain family. To our knowledge, CH4-based heterodimers have not been previously reported.
机译：双特异性抗体（bsAbs）对新型抗体疗法的发展非常重要，重链（Hc）异二聚体代表了主要的双特异性药物候选物。用于产生Hc异二聚体的当前技术是次优的，并且经常遭受构成纯化挑战的同二聚体的污染。在这里，我们介绍了一种基于仿生学的新技术，其中两个或多个免疫球蛋白（Ig）恒定域对的蛋白质-蛋白质界面部分或全部交换以设计新的异二聚体域。该方法可应用于各种Ig，以设计Fc异二聚体和bsAb。我们研究了人IgA CH3，IgD CH3，IgG1 CH3，IgM CH4，T细胞受体（TCR）α/β和TCRγ/δ恒定域对的接口，发现它们成功驱动人IgG1 CH3或IgM CH4异二聚化至与参考方法相似或更高的水平。 X射线晶体学证实了TCRα/β恒定域对与IgG1 CH3同型二聚体之间的全面界面交换，并被用于工程化bsAb的实例用于癌症治疗。通过结合界面交换，不对称蛋白A结合和scFv×Fab形式，将亲本抗体对迅速重新格式化为可扩展的bsAb，而该同型抗体不含同二聚体痕迹。总而言之，我们成功构建了几种新的基于CH3或CH4的异二聚体，可能对设计基于bsAb的新疗法有用，并且我们希望我们的方法可在Ig恒定域家族中广泛实施。据我们所知，以前没有报道过基于CH4的异二聚体。

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