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用于生物医学应用的纳米颗粒制备的聚乙二醇-单克隆抗体缀合物的研究。

Studies on polyethylene glycol-monoclonal antibody conjugates for fabrication of nanoparticles for biomedical applications.

作者信息

Fisusi Funmilola, Brandy Nailah, Wu Jingbo, Akala Emmanuel O

机构信息

Department of Pharmaceutical Sciences, Center for Drug Research and Development, College of Pharmacy, Howard University, Washington, DC.

出版信息

J Nanosci Nanomed. 2020 Jul;4(2):1-9. Epub 2020 Feb 3.

PMID:33564752
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7869852/
Abstract

OBJECTIVE

The objective of this work is to synthesize and characterize PEGylated monoclonal antibody using the reactivity of oligosaccharide residues in the Fc region of trastuzumab and pertuzumab with a view to preserving their activities.

METHODS

The hydrazide-functionalized PEG monomethacrylate was synthesized and reacted with NaIO-generated aldehyde groups on glycans in the Fc-domain of trastuzumab and pertuzumab. The conjugates were purified by HPLC. SAMSA-fluorescein substitution method and MALDI MS spectroscopy were used to determine the number of PEG per antibody. Preliminary biological studies involved antiproliferative studies and binding (flow cytometry) following treatments with SKBR3 (HER2-overexpressing) cells and the control.

RESULTS

H NMR and C NMR confirmed the formation of hydrazide-functionalized PEG monomethacrylate. MALDI mass-spectrometry showed that there are two PEGs per each antibody and it appears more reliable than the degree of SAMSA-fluorescein substitution method. HER-2 binding assay showed that PEGylated monoclonal antibody bound less efficiently to SKBR3 (high HER-2 expressing) cells than unmodified trastuzumab and pertuzumab. growth inhibitory effects of unmodified monoclonal antibodies increased with increase in concentration; while the growth inhibitory effects of PEGylated monoclonal antibodies also increased (but less than the pure antibody) with concentration and it appeared to be more active than unmodified mAbs at higher concentration.

CONCLUSION

The results indicate that PEG can be site-specifically attached the oxidized glycans in the Fc domain of monoclonal antibodies but the process needs further optimization in terms of PEG size and biological testing at each stage of development.

摘要

目的

本研究旨在利用曲妥珠单抗和帕妥珠单抗Fc区域寡糖残基的反应性合成并表征聚乙二醇化单克隆抗体，以保留其活性。

方法

合成了酰肼功能化的聚乙二醇单甲基丙烯酸酯，并使其与曲妥珠单抗和帕妥珠单抗Fc结构域聚糖上由高碘酸钠生成的醛基反应。通过高效液相色谱法纯化缀合物。采用SAMSA-荧光素取代法和基质辅助激光解吸电离质谱法测定每个抗体上聚乙二醇的数量。初步生物学研究包括用SKBR3（HER2过表达）细胞和对照进行处理后的抗增殖研究和结合（流式细胞术）。

结果

1H NMR和13C NMR证实了酰肼功能化聚乙二醇单甲基丙烯酸酯的形成。基质辅助激光解吸电离质谱显示每个抗体有两个聚乙二醇，并且它似乎比SAMSA-荧光素取代法更可靠。HER-2结合试验表明，聚乙二醇化单克隆抗体与SKBR3（高HER-2表达）细胞的结合效率低于未修饰的曲妥珠单抗和帕妥珠单抗。未修饰单克隆抗体的生长抑制作用随浓度增加而增强；而聚乙二醇化单克隆抗体的生长抑制作用也随浓度增加（但低于纯抗体），并且在较高浓度下似乎比未修饰的单克隆抗体更具活性。

结论

结果表明聚乙二醇可位点特异性地连接到单克隆抗体Fc结构域的氧化聚糖上，但该过程在聚乙二醇大小和开发各阶段的生物学测试方面需要进一步优化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c92/7869852/cd05991103d8/nihms-1655275-f0012.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6c92/7869852/de9069876c04/nihms-1655275-f0009.jpg
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