Highly aggregated antibody therapeutics can enhance the in vitro innate and late-stage T-cell immune responses.
Highly aggregated antibody therapeutics can enhance the in vitro innate and late-stage T-cell immune responses.
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DOI：
10.1074/jbc.m111.330902
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发表时间：
2012-07-20
期刊：
影响因子：
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通讯作者：
Jawa V
中科院分区：
文献类型：
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作者：
Joubert MK;Hokom M;Eakin C;Zhou L;Deshpande M;Baker MP;Goletz TJ;Kerwin BA;Chirmule N;Narhi LO;Jawa V
背景：聚集的生物治疗剂具有诱导免疫应答的潜力。结果：聚集体能增强PBMC的天然免疫和获得性免疫应答。结论：反应取决于聚合物类型、单体的免疫原性、供体免疫状态和体外试验中的高颗粒数。意义：这是第一项显示聚集体特征对PBMC潜在免疫应答影响的研究。生物治疗剂的聚集具有诱导免疫原性应答的潜力。在此，我们表明，先前产生并确定含有多种属性的聚集的治疗性抗体（Joubert，M. K.，罗，Q，Nashed-Samuel，Y.，Wypych，J.，和Narhi，L. O.（2011）J.Biol.Chem.286，25118-25133），可以增强初始人外周血单核细胞群体的体外先天免疫应答。这种反应取决于聚集体类型、单体的固有免疫原性和供体反应性，并且需要大量颗粒，远高于在市售制剂中检测到的颗粒，至少在该体外系统中是这样。我们提出了一个细胞因子的签名作为一个潜在的生物标志物在体外外周血单核细胞聚集反应。细胞因子包括IL-1β、IL-6、IL-10、MCP-1、MIP-1α、MIP-1β、MMP-2和TNF-α。IL-6和IL-10可能对长期免疫应答具有免疫抑制作用。与其他方法制备的聚集体相比，通过搅拌制备的聚集体诱导了最高的响应。2-10 μm范围内的粒度和保留一些折叠结构与响应增加相关。发现先天期聚集体激活的机制通过特异性细胞表面受体（toll样受体TLR-2和TLR-4、Fcγ R和补体系统）发生。先天性信号显示出进展为以T细胞增殖和T细胞细胞因子分泌为特征的适应性T细胞应答。研究聚集体诱导细胞因子特征作为免疫应答生物标志物的能力对于确定其免疫原性风险至关重要。
Background: Aggregated biotherapeutics have the potential to induce an immune response. Results: Aggregates can enhance innate and adaptive immune responses of PBMC. Conclusion: The response depends on aggregate type, immunogenicity of the monomer, donor immune status, and high particle numbers in the in vitro assay. Significance: This is the first study showing the impact of aggregate characteristics on the potential immune response of PBMC. Aggregation of biotherapeutics has the potential to induce an immunogenic response. Here, we show that aggregated therapeutic antibodies, previously generated and determined to contain a variety of attributes (Joubert, M. K., Luo, Q., Nashed-Samuel, Y., Wypych, J., and Narhi, L. O. (2011) J. Biol. Chem. 286, 25118–25133), can enhance the in vitro innate immune response of a population of naive human peripheral blood mononuclear cells. This response depended on the aggregate type, inherent immunogenicity of the monomer, and donor responsiveness, and required a high number of particles, well above that detected in marketed drug products, at least in this in vitro system. We propose a cytokine signature as a potential biomarker of the in vitro peripheral blood mononuclear cell response to aggregates. The cytokines include IL-1β, IL-6, IL-10, MCP-1, MIP-1α, MIP-1β, MMP-2, and TNF-α. IL-6 and IL-10 might have an immunosuppressive effect on the long term immune response. Aggregates made by stirring induced the highest response compared with aggregates made by other methods. Particle size in the 2–10 μm range and the retention of some folded structure were associated with an increased response. The mechanism of aggregate activation at the innate phase was found to occur through specific cell surface receptors (the toll-like receptors TLR-2 and TLR-4, FcγRs, and the complement system). The innate signal was shown to progress to an adaptive T-cell response characterized by T-cell proliferation and secretion of T-cell cytokines. Investigating the ability of aggregates to induce cytokine signatures as biomarkers of immune responses is essential for determining their risk of immunogenicity.