Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity
Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity
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IVIg 的受控四 Fc 唾液酸化导致候选药物具有一致增强的抗炎活性
DOI：
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发表时间：
2015
影响因子：
11.1
通讯作者：
C. Bosques
中科院分区：
文献类型：
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作者：
N. Washburn;I. Schwab;D. Ortiz;N. Bhatnagar;J. Lansing;Amy A. Medeiros;S. Tyler;D. Mekala;E. Cochran;H. Sarvaiya;Kevin Garofalo;Robin Meccariello;J. Meador;L. Rutitzky;B. Schultes;L. Ling;W. Avery;F. Nimmerjahn;A. Manning;Ganesh V. Kaundinya;C. Bosques
IgG片段可结晶结构域（Fc）唾液酸化已经成为调节抗体抗炎活性的重要但有争议的概念。此外，将该概念转化为有效的抗炎治疗剂受到难以产生适合人类使用的唾液酸化产物的阻碍。据我们所知，我们首次描述了一种稳健的、可扩展的方法的开发，该方法用于产生具有最大Fc唾液酸化且没有不需要的修饰的唾液酸化静脉内免疫球蛋白（IVIg）候选药物。通过使用广泛的理化分析和体内模型，我们已经验证了这种临床候选药物的质量和有效的抗炎活性。该报告不仅证实了IgG-Fc唾液酸化的争议性抗炎活性，而且据我们所知，它还代表了第一种唾液酸化IVIg制剂，具有适用于临床开发的一致抗炎效力。尽管静脉注射免疫球蛋白（IVIg）对炎症性疾病具有有益的治疗作用，但一致的治疗功效和效力仍然是使用IVIg的患者和医生的主要限制。这些限制激发了产生治疗替代品的愿望，这些替代品可以利用IVIg的广泛作用机制，同时提高治疗一致性和效力。片段可结晶结构域（Fc）唾液酸化的重要抗炎作用的鉴定为开发更有效的IG疗法提供了机会。然而，将这一概念转化为有效的抗炎治疗剂受到难以产生用于临床使用的合适的唾液酸化产物的阻碍。因此，据我们所知，我们着手开发第一种稳健且可扩展的方法，用于产生具有最大Fc唾液酸化且没有IVIg混合物的不必要改变的合格的唾液酸化IVIg候选药物。在这里，我们描述了一种受控的酶促、可扩展的工艺，以生产四-Fc-唾液酸化（s4-IVIg）IVIg候选药物及其在广泛的分析测定中的资格，包括理化、药代动力学、生物分布和体内炎症动物模型。我们对这种候选药物的体内表征显示，在不同的动物模型中，其抗炎活性比IVIg高出10倍。据我们所知，该候选药物代表了第一个适合临床使用的s4-IVIg;它也是一种有价值的治疗替代品，具有更一致和有效的抗炎活性。
Significance IgG fragment crystallizable domain (Fc) sialylation has emerged as an important but controversial concept for regulating anti-inflammatory activity of antibodies. Moreover, translating this concept to potent anti-inflammatory therapeutics has been hampered by the difficulty of generating suitable sialylated products for human use. We describe for the first time, to our knowledge, the development of a robust, scalable process to generate a sialylated intravenous immunoglobulin (IVIg) drug candidate with maximum Fc sialylation devoid of unwanted modifications. By using a wide panel of physicochemical analytics and in vivo models, we have validated the quality and potent anti-inflammatory activity of this clinical candidate. This report not only confirms the controversial anti-inflammatory activity of IgG-Fc sialylation, it also represents the first sialylated IVIg preparation, to our knowledge, with consistent anti-inflammatory potency suitable for clinical development. Despite the beneficial therapeutic effects of intravenous immunoglobulin (IVIg) in inflammatory diseases, consistent therapeutic efficacy and potency remain major limitations for patients and physicians using IVIg. These limitations have stimulated a desire to generate therapeutic alternatives that could leverage the broad mechanisms of action of IVIg while improving therapeutic consistency and potency. The identification of the important anti-inflammatory role of fragment crystallizable domain (Fc) sialylation has presented an opportunity to develop more potent Ig therapies. However, translating this concept to potent anti-inflammatory therapeutics has been hampered by the difficulty of generating suitable sialylated products for clinical use. Therefore, we set out to develop the first, to our knowledge, robust and scalable process for generating a well-qualified sialylated IVIg drug candidate with maximum Fc sialylation devoid of unwanted alterations to the IVIg mixture. Here, we describe a controlled enzymatic, scalable process to produce a tetra-Fc–sialylated (s4-IVIg) IVIg drug candidate and its qualification across a wide panel of analytic assays, including physicochemical, pharmacokinetic, biodistribution, and in vivo animal models of inflammation. Our in vivo characterization of this drug candidate revealed consistent, enhanced anti-inflammatory activity up to 10-fold higher than IVIg across different animal models. To our knowledge, this candidate represents the first s4-IVIg suitable for clinical use; it is also a valuable therapeutic alternative with more consistent and potent anti-inflammatory activity.
影响因子：
15.9
作者：
Schmidt, AM;Du Yan, S;Stern, DM
通讯作者：
Stern, DM
影响因子：
15.9
作者：
Hess, Constanze;Winkler, Andre;Ehlers, Marc
通讯作者：
Ehlers, Marc