Influence of molecular size on tissue distribution of antibody fragments
Influence of molecular size on tissue distribution of antibody fragments
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DOI：
10.1080/19420862.2015.1111497
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发表时间：
2016-01-02
期刊：
影响因子：
5.3
通讯作者：
Shah, Dhaval K.
中科院分区：
文献类型：
--
作者：
Li, Zhe;Krippendorff, Ben-Fillippo;Shah, Dhaval K.
生物分布系数（BC）允许根据血浆药代动力学估计蛋白质的组织浓度。我们之前已经建立了单克隆抗体的BC值。在这里，这个概念通过蛋白质大小和BC值之间关系的发展得到了扩展。这种关系是通过从已发表的生物分布研究中推导出已知分子量的各种抗体片段的BC值来建立的。我们发现分子量和BC值之间存在简单的指数关系，可以仅根据分子量预测蛋白质的组织分布。这种关系通过对未用于建立这种关系的4个抗体片段的BC值的先验预测得到验证。该关系还被用于得出所有组织的BC50值，即分子量的增加会导致组织对蛋白质的吸收减少50%。大多数组织的BC50值接近35kDa。根据BC与分子大小的关系来估计抗体片段的组织分布，可以更好地理解组织中生物制剂的浓度对疗效或毒性的影响。这种关系也可以应用于合理开发新的生物治疗方式，具有最佳的生物分布特性，以针对（或避免）特定组织。
Biodistribution coefficients (BC) allow estimation of the tissue concentrations of proteins based on the plasma pharmacokinetics. We have previously established the BC values for monoclonal antibodies. Here, this concept is extended by development of a relationship between protein size and BC values. The relationship was built by deriving the BC values for various antibody fragments of known molecular weight from published biodistribution studies. We found that there exists a simple exponential relationship between molecular weight and BC values that allows the prediction of tissue distribution of proteins based on molecular weight alone. The relationship was validated by a priori predicting BC values of 4 antibody fragments that were not used in building the relationship. The relationship was also used to derive BC50 values for all the tissues, which is the molecular weight increase that would result in 50% reduction in tissue uptake of a protein. The BC50 values for most tissues were found to be similar to 35kDa. An ability to estimate tissue distribution of antibody fragments based on the BC vs. molecular size relationship established here may allow better understanding of the biologics concentrations in tissues responsible for efficacy or toxicity. This relationship can also be applied for rational development of new biotherapeutic modalities with optimal biodistribution properties to target (or avoid) specific tissues.