Sastyarina Yurika, Firdaus Ade Rizqi Ridwan, Nafisah Zuhrotun, Hardianto Ari, Yusuf Muhammad, Ramli Martalena, Mutalib Abdul, Soedjanaatmadja Ukun Ms
Faculty of Pharmacy, Universitas Mulawarman, Samarinda, Indonesia.
Department of Chemistry, Faculty of Mathematics and Natural Science, Universitas Padjadjaran, Bandung, Indonesia.
Bioinform Biol Insights. 2021 Mar 25;15:11779322211002174. doi: 10.1177/11779322211002174. eCollection 2021.
Lung cancer is one of the leading causes of cancer-related deaths in the world among both men and women. Several studies in the literature report that overexpression and mutation of the epidermal growth factor receptor (EGFR) are implicated in the pathogenesis of some lung cancers. Nimotuzumab is a humanized monoclonal antibody (mAb) that inhibits EGF binding because it binds to the extracellular domain of the EGFR. Nimotuzumab requires bivalent binding for stable attachment to cellular surface, which leads to nimotuzumab selectively binding to cells that express mAbs of moderate to high EGFR levels, and this could explain its low toxicity. This property has an advantage for development of nimotuzumab as a therapeutic and diagnostic agent. Monoclonal antibodies are large in size (150 kDa), thus penetrating slowly and residing in the blood for extended periods of time (from days to weeks); their use in imaging studies can result in low signal-to-background ratios and poor image quality. A reduction in the size of the immunoglobulin molecule has also been proposed as a means for increasing tumor penetration by mAbs. Nevertheless, it is known that the penetration of mAb into tumor cell is slow, due to its high molecular weight. Therefore, mAb is not very attractive to be used for imaging diagnostic purpose because of its kinetics and potential to elicit antibody response. The objective of this research was to study the homology modeling of a simpler functional molecule based on nimotuzumab, which consists of 2 antigen-binding fragments (Fab), namely, F(ab'), using MODELER. The crystal structure of Fab of nimotuzumab from protein data bank was used as a template to construct the model of F(ab'). Molecular dynamic simulation was performed to evaluate the stability of F(ab') and conformational changes of F(ab') in simulation. The result showed the dynamic behavior of antigen-binding site region of F(ab') throughout simulation. This result is expected to be useful in the further development of F(ab') fragment nimotuzumab as a lung cancer diagnostic.
肺癌是全球男性和女性癌症相关死亡的主要原因之一。文献中的多项研究报告称，表皮生长因子受体（EGFR）的过表达和突变与某些肺癌的发病机制有关。尼妥珠单抗是一种人源化单克隆抗体（mAb），它通过与EGFR的细胞外结构域结合来抑制EGF结合。尼妥珠单抗需要二价结合才能稳定附着于细胞表面，这使得尼妥珠单抗选择性地结合表达中度至高度EGFR水平单克隆抗体的细胞，这也可以解释其低毒性。这一特性对尼妥珠单抗作为治疗和诊断药物的开发具有优势。单克隆抗体尺寸较大（150 kDa），因此穿透缓慢且在血液中停留较长时间（从数天到数周）；它们在成像研究中的使用可能导致低信噪比和较差的图像质量。也有人提出减小免疫球蛋白分子的大小作为增加单克隆抗体肿瘤穿透力的一种方法。然而，由于其高分子量，已知单克隆抗体进入肿瘤细胞的速度较慢。因此，由于其动力学特性和引发抗体反应的可能性，单克隆抗体不太适合用于成像诊断目的。本研究的目的是使用MODELER研究基于尼妥珠单抗的更简单功能分子的同源建模，该分子由2个抗原结合片段（Fab）组成，即F(ab')。来自蛋白质数据库的尼妥珠单抗Fab的晶体结构用作构建F(ab')模型的模板。进行分子动力学模拟以评估F(ab')的稳定性以及模拟过程中F(ab')的构象变化。结果显示了整个模拟过程中F(ab')抗原结合位点区域的动态行为。该结果有望对F(ab')片段尼妥珠单抗作为肺癌诊断剂的进一步开发有用。
