Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech Research and Early Development, South San Francisco, California 94080, USA.
Bioconjug Chem. 2010 Dec 15;21(12):2153-63. doi: 10.1021/bc100261d. Epub 2010 Nov 5.
Antibody pharmacokinetics and pharmacodynamics are often governed by biological processes such as binding to antigens and other cognate receptors. Emphasis must also be placed, however, on fundamental physicochemical properties that define antibodies as complex macromolecules, including shape, size, hydrophobicity, and charge. Electrostatic interactions between anionic cell membranes and the predominantly positive surface charge of most antibodies can influence blood concentration and tissue disposition kinetics in a manner that is independent of antigen recognition. In this context, the deliberate modification of antibodies by chemical means has been exploited as a valuable preclinical research tool to investigate the relationship between net molecular charge and biological disposition. Findings from these exploratory investigations may be summarized as follows: (I) shifts in isoelectric point of approximately one pI unit or more can produce measurable changes in tissue distribution and kinetics, (II) increases in net positive charge generally result in increased tissue retention and increased blood clearance, and (III) decreases in net positive charge generally result in decreased tissue retention and increased whole body clearance. Understanding electrostatic interactions between antibodies and biological matrices holds relevance in biotechnology, especially with regard to the development of immunoconjugates. The guiding principles and knowledge gained from preclinical evaluation of chemically modified antibodies will be discussed and placed in the context of therapeutic antibodies that are currently marketed or under development, with a particular emphasis on pharmacokinetic and disposition properties.
抗体的药代动力学和药效动力学通常受生物过程的控制，如与抗原和其他同源受体的结合。然而，还必须强调定义抗体为复杂大分子的基本物理化学性质，包括形状、大小、疏水性和电荷。阴离子细胞膜与大多数抗体的主要正表面电荷之间的静电相互作用可以以与抗原识别无关的方式影响血液浓度和组织处置动力学。在这种情况下，通过化学手段故意修饰抗体已被用作有价值的临床前研究工具，以研究净分子电荷与生物处置之间的关系。这些探索性研究的结果可以总结如下：(I) 等电点约改变一个 pI 单位或更多可以产生可测量的组织分布和动力学变化，(II) 净正电荷增加通常会导致组织保留增加和血液清除率增加，以及 (III) 净正电荷减少通常会导致组织保留减少和全身清除率增加。了解抗体与生物基质之间的静电相互作用在生物技术中具有相关性，特别是在免疫偶联物的开发方面。本文将讨论从化学修饰抗体的临床前评估中获得的指导原则和知识，并将其置于当前市售或正在开发的治疗性抗体的背景下，特别强调药代动力学和处置特性。
