降低水性或屏蔽CH2的水性区域减弱了低pH诱导的IgG4聚合
Qiang Wu1,2, Chunlai Cao2,3, Suzhen Wei3
1School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China.
Frontiers in bioengineering and biotechnology
|September 15, 2023
概括
低pH条件会增加治疗性单克隆抗体 (mAbs) 的聚合. 在mAb1-IgG4的CH2域中的突变和稳定剂减少了这种聚合,为蛋白质药物开发提供了策略.
科学领域:
- 生物制药的发展.
- 蛋白质化学 蛋白质化学
- 免疫学 免疫学 免疫学
背景情况:
- 蛋白质聚合是开发治疗性单克隆抗体 (mAbs) 的重要障碍.
- 在蛋白质A染色体和病毒失活等制造工艺中常见的低pH条件,大大增加了抗体聚合.
- 在低pH暴露下,IgG4亚类抗体mAb1-IgG4表现出明显的聚集倾向.
研究的目的:
- 为了研究低pH诱导的聚合在mAb1-IgG4.4背后的分子机制.
- 鉴定IgG4基蛋白疗法中减轻聚合的策略.
主要方法:
- 在低pH压力下分析mAb1-IgG4聚合.
- 在CH2域的位点定向突变发生.
- 评估蛋白质稳定剂 (糖糖,甘) 对聚合物的影响.
主要成果:
- 低pH诱导的mAb1-IgG4聚合主要取决于Fc区域的稳定性,特别是CH2域.
- 在CH2域中的L309E,Q311D和Q311E突变通过降低疏水性,显著降低了聚合倾向.
- 诸如糖和糖之类的辅助剂通过屏蔽疏水区域并增强蛋白质稳定性,有效地减弱了低pH诱导的聚合.
结论:
- 在控制低pH诱导的IgG4抗体聚合时,CH2域的稳定性至关重要.
- 向突变和蛋白质稳定剂的使用是管理治疗性蛋白质开发中的聚合的可行策略.
- 这些发现为改善基于IgG4的生物制剂的开发能力提供了实际方法.
相关概念视频
Transcytosis of IgG
2.8K
Transcytosis is the process in which molecules are internalized by endocytosis, transported across the cell, and released through exocytosis from the opposite end of the cell. Molecules such as insulin, immunoglobulins, and certain nutrients are transferred through the recycling endosomes by recycling and transcytosis.
IgG molecules from a mother undergo transcytosis starting around 13 weeks of gestation. The amount of IgG transferred and entering the fetal blood circulation increases with...
IgG molecules from a mother undergo transcytosis starting around 13 weeks of gestation. The amount of IgG transferred and entering the fetal blood circulation increases with...
2.8K
Mixtures of Acids
720
The pH of a solution containing an acid can be determined using its acid dissociation constant and initial concentration. If a solution contains two different acids, then its pH can be determined using one of several methods depending on the relative strength of the acids and their dissociation constants.
In a strong and weak acid mixture, the strong acid dissociates completely and becomes a source of almost all the hydronium ions present in the solution. In contrast, the weak acid shows...
In a strong and weak acid mixture, the strong acid dissociates completely and becomes a source of almost all the hydronium ions present in the solution. In contrast, the weak acid shows...
720
Antibody Structure
60.3K
Overview
Antibodies, also known as immunoglobulins (Ig), are essential players of the adaptive immune system. These antigen-binding proteins are produced by B cells and make up 20 percent of the total blood plasma by weight. In mammals, antibodies fall into five different classes, which each elicits a different biological response upon antigen binding.
The Y-Shaped Structure of Antibodies Consists of Four Polypeptide Chains
Antibodies consist of four polypeptide chains: two identical heavy...
Antibodies, also known as immunoglobulins (Ig), are essential players of the adaptive immune system. These antigen-binding proteins are produced by B cells and make up 20 percent of the total blood plasma by weight. In mammals, antibodies fall into five different classes, which each elicits a different biological response upon antigen binding.
The Y-Shaped Structure of Antibodies Consists of Four Polypeptide Chains
Antibodies consist of four polypeptide chains: two identical heavy...
60.3K
Factors Affecting Dissolution: Drug pKa, Lipophilicity and GI pH
1.5K
Drug absorption within the gastrointestinal (GI) tract is a complex process influenced by several critical factors, including the site pH, the drug's dissociation constant (pKa), and the drug's lipophilicity. The GI tract exhibits a pH gradient, with an acidic environment in the stomach and a more alkaline environment in the small intestine. This pH variation directly affects the ionization state of drugs.
A drug's pKa and the pH of the gastrointestinal (GI) tract play crucial roles...
A drug's pKa and the pH of the gastrointestinal (GI) tract play crucial roles...
1.5K
Alkyl Halides
16.9K
Structural Properties
Alkyl halides are halogen-substituted alkanes wherein one or more hydrogen atoms of an alkane is replaced by a halogen atom such as fluorine, chlorine, bromine, or iodine. The carbon atom in an alkyl halide is bonded to the halogen atom, which is sp3-hybridized and exhibits a tetrahedral shape.
Unlike alkyl halides, compounds in which a halogen atom is bonded to an sp2 -hybridized carbon atom of a carbon-carbon double bond (C=C) are called vinyl halides. Whereas aryl...
Alkyl halides are halogen-substituted alkanes wherein one or more hydrogen atoms of an alkane is replaced by a halogen atom such as fluorine, chlorine, bromine, or iodine. The carbon atom in an alkyl halide is bonded to the halogen atom, which is sp3-hybridized and exhibits a tetrahedral shape.
Unlike alkyl halides, compounds in which a halogen atom is bonded to an sp2 -hybridized carbon atom of a carbon-carbon double bond (C=C) are called vinyl halides. Whereas aryl...
16.9K
Inductive Effects on Chemical Shift: Overview
1.1K
The protons in unsubstituted alkanes are strongly shielded with chemical shifts below 1.8 ppm. Methine, methylene, and methyl protons appear at approximately 1.7, 1.2 and 0.7 ppm, while the proton signal from methane appears at 0.23 ppm. An electronegative substituent, such as chlorine, withdraws the electron density from the protons, increasing their chemical shift. Progressive substitution of the hydrogens in methane by chlorine shifts the proton signals increasingly downfield, to 3.05 ppm in...
1.1K


