A broad range of Fab stabilities within a host of therapeutic IgGs
A broad range of Fab stabilities within a host of therapeutic IgGs
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DOI：
10.1016/j.bbrc.2007.02.042
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发表时间：
2007-04-13
影响因子：
3.1
通讯作者：
Demarest, Stephen J.
中科院分区：
文献类型：
--
作者：
Garber, Ellen;Demarest, Stephen J.
虽然免疫球蛋白的功能性质已为人所熟知，但关于完整的免疫球蛋白分子的稳定性的报道却很少。然而，稳定性是开发用于治疗或诊断应用的抗体的要求。高变量抗原结合区(FV)是相同亚类的免疫球蛋白之间稳定性差异的原因。为了确定预期的人(化)抗体的稳定性范围，对来自不同内部计划的17个人(化)抗体进行了差示扫描量热法。这些抗体的抗原结合片段(Fab)呈现热展开转变，中点(T(M)S)从57℃到82℃不等。Fab稳定性很低的抗体聚集和表达很差。FAB的不稳定性通常与高水平的罕见观察到的氨基酸或CDR环长有关，特别是在可变重链结构域中。总体而言，这项研究提供了免疫球蛋白的热稳定性范围，并为开发抗体诊断或治疗提供了可能的稳定性指南。(C)2007 Elsevier Inc.保留所有权利。
Although the functional properties of IgGs are well known, little has been published concerning the stability of whole IgG molecules. Stability is, however, a requirement for the development of antibodies For therapeutic or diagnostic applications. The hypervariable antigen-binding region (Fv) is responsible for stability variations between IgGs of identical subclass. To determine the range of stabilities that may be expected for human(ized) antibodies, differential scanning calorimetry was performed on 17 human(ized) antibodies from various in-house programs. The antigen-binding fragments (Fabs) of these antibodies exhibited thermal unfolding transitions with midpoints (T(M)s) varying from 57 to 82 degrees C. Antibodies with very low Fab stabilities were found to aggregate and express poorly. Fab instability was often associated with high levels of uncommonly observed amino acids or CDR loop lengths particularly within the variable heavy chain domain. Overall, the study provides a thermostability range for IgGs and suggests possible stability guidelines for developing antibody diagnostics or therapeutics. (c) 2007 Elsevier Inc. All rights reserved.