Development of a two-part strategy to identify a therapeutic human bispecific antibody that inhibits IgE receptor signaling.
Development of a two-part strategy to identify a therapeutic human bispecific antibody that inhibits IgE receptor signaling.
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DOI：
10.1074/jbc.m110.113910
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发表时间：
2010-07-02
期刊：
影响因子：
--
通讯作者：
Wu LC
中科院分区：
文献类型：
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作者：
Jackman J;Chen Y;Huang A;Moffat B;Scheer JM;Leong SR;Lee WP;Zhang J;Sharma N;Lu Y;Iyer S;Shields RL;Chiang N;Bauer MC;Wadley D;Roose-Girma M;Vandlen R;Yansura DG;Wu Y;Wu LC
双特异性抗体作为治疗人类疾病的药物具有巨大的临床潜力，但由于难以识别具有良好的药代动力学特性和易于大规模生产的双特异性抗体形式而阻碍了其广泛应用。此前，利用重链节孔突变和单一共同轻链的抗体技术的发展使小规模产生人类全长双特异性抗体成为可能。在这里，我们通过开发一种两部分的双特异性抗体发现策略来扩展技术，该策略有助于概念验证研究和临床候选抗体的生成。我们的方案包括高效小规模产生缺乏共同轻链的双特异性抗体和用于概念验证研究的铰链二硫化物，以及鉴定用于大规模生产的共同轻链双特异性抗体，并以高纯度和高产量进行生产。我们已经应用这项技术来产生一种双特异性抗体，适合作为人类治疗药物开发。该抗体通过将FcϵRI与抑制性受体FcϵRIIb交联，直接抑制肥大细胞和嗜碱性粒细胞上高亲和力Ig E受体FcγRI的激活，这一方法对哮喘和其他过敏性疾病具有很强的治疗潜力。我们生产人类双特异性全长抗体的方法使双特异性抗体能够在临床上应用于哮喘的有效治疗途径。
The development of bispecific antibodies as therapeutic agents for human diseases has great clinical potential, but broad application has been hindered by the difficulty of identifying bispecific antibody formats that exhibit favorable pharmacokinetic properties and ease of large-scale manufacturing. Previously, the development of an antibody technology utilizing heavy chain knobs-into-holes mutations and a single common light chain enabled the small-scale generation of human full-length bispecific antibodies. Here we have extended the technology by developing a two-part bispecific antibody discovery strategy that facilitates proof-of-concept studies and clinical candidate antibody generation. Our scheme consists of the efficient small-scale generation of bispecific antibodies lacking a common light chain and the hinge disulfides for proof-of-concept studies coupled with the identification of a common light chain bispecific antibody for large-scale production with high purity and yield. We have applied this technology to generate a bispecific antibody suitable for development as a human therapeutic. This antibody directly inhibits the activation of the high affinity IgE receptor FcϵRI on mast cells and basophils by cross-linking FcϵRI with the inhibitory receptor FcγRIIb, an approach that has strong therapeutic potential for asthma and other allergic diseases. Our approach for producing human bispecific full-length antibodies enables the clinical application of bispecific antibodies to a validated therapeutic pathway in asthma.