A versatile design platform for glycoengineering therapeutic antibodies.
A versatile design platform for glycoengineering therapeutic antibodies.
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DOI：
10.1080/19420862.2022.2095704
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发表时间：
2022-01
期刊：
影响因子：
5.3
通讯作者：
Spangler JB
中科院分区：
文献类型：
--
作者：
Ludwig SD;Bernstein ZJ;Agatemor C;Dammen-Brower K;Ruffolo J;Rosas JM;Post JD;Cole RN;Yarema KJ;Spangler JB
糖基化模式的操纵，即，糖工程（glycoengineering）被并入治疗性抗体开发工作流程中以确保临床安全性，并且该方法也已用于调节抗体药物的生物活性、功能或药理学性质。鉴于大多数现有的糖工程策略集中在免疫球蛋白G（IgG）抗体的恒定结构域中发现的典型聚糖，我们报告了一种新的策略，以利用可变结构域中未开发的非典型糖基化模式的潜力，其天然存在于15%至25%的IgG抗体中。将糖基化位点添加到两种功能不同的白细胞介素-2结合单克隆抗体的抗原结合区。我们使用计算工具将各种N-糖基化共有序列合理地安装到抗体可变结构域中，产生这些分子的“糖变体”。引人注目的是，几乎所有的糖变体都在其新安装的N-聚糖位点成功地糖基化，而不降低抗体的天然功能。重要的是，与亲本抗体相比，某些糖变体表现出修饰的活性，显示了我们的糖工程化策略调节参与多组分受体系统的抗体的生物学功能的潜力。最后，当与高通量唾液酸前体结合时，具有两个安装的糖基化位点的糖变体表现出上级体内半衰期。总的来说，这些发现验证了一种通用的糖工程策略，该策略将非典型糖基化引入治疗性抗体中，以提高其功效，并且在某些情况下，在药物开发过程的早期调节其活性。
Manipulation of glycosylation patterns, i.e., glycoengineering, is incorporated in the therapeutic antibody development workflow to ensure clinical safety, and this approach has also been used to modulate the biological activities, functions, or pharmacological properties of antibody drugs. Whereas most existing glycoengineering strategies focus on the canonical glycans found in the constant domain of immunoglobulin G (IgG) antibodies, we report a new strategy to leverage the untapped potential of atypical glycosylation patterns in the variable domains, which naturally occur in 15% to 25% of IgG antibodies. Glycosylation sites were added to the antigen-binding regions of two functionally divergent, interleukin-2-binding monoclonal antibodies. We used computational tools to rationally install various N-glycosylation consensus sequences into the antibody variable domains, creating “glycovariants” of these molecules. Strikingly, almost all the glycovariants were successfully glycosylated at their newly installed N-glycan sites, without reduction of the antibody’s native function. Importantly, certain glycovariants exhibited modified activities compared to the parent antibody, showing the potential of our glycoengineering strategy to modulate biological function of antibodies involved in multi-component receptor systems. Finally, when coupled with a high-flux sialic acid precursor, a glycovariant with two installed glycosylation sites demonstrated superior in vivo half-life. Collectively, these findings validate a versatile glycoengineering strategy that introduces atypical glycosylation into therapeutic antibodies in order to improve their efficacy and, in certain instances, modulate their activity early in the drug development process.
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DOI：
10.1073/pnas.0909384107
发表时间：
2010-02-02
影响因子：
11.1
作者：
Letourneau, Sven;van Leeuwen, Ester M. M.;Boyman, Onur
通讯作者：
Boyman, Onur
DOI：
10.2174/138620709789104915
发表时间：
2009-09-01
影响因子：
1.8
作者：
Concepcion, Joy;Witte, Krista;Tan, Hong
通讯作者：
Tan, Hong
影响因子：
14.8
作者：
通讯作者：
--
单克隆抗体和FC融合蛋白的药代动力学。
影响因子：
21.1
作者：
Liu L
通讯作者：
Liu L
DOI：
10.1002/psp4.12224
发表时间：
2017-09
期刊：
CPT: pharmacometrics & systems pharmacology
影响因子：
--
作者：
Ryman JT;Meibohm B
通讯作者：
Meibohm B