Development and biological assessment of MMAE-trastuzumab antibody-drug conjugates (ADCs)

Yaghoubi, Sajad and Gharibi, Tohid and karimi, Mohammad Hossein and Sadeqi Nezhad, Muhammad and Seifalian, Alexander and Tavakkol, Reza and Bagheri, Nader and Dezhkam, Asiyeh and Abdollahpour-Alitappeh, Meghdad (2021) Development and biological assessment of MMAE-trastuzumab antibody-drug conjugates (ADCs). Breast Cancer, 28 (1). pp. 216-225. ISSN 13406868

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Abstract

Background: Trastuzumab, a humanized monoclonal antibody targeting Human Epidermal growth factor Receptor 2 (HER2), is a therapeutic option used for the treatment of patients with HER2-overexpressing breast cancers. The primary purpose of the present study was to establish a trastuzumab-based antibody drug conjugate (ADC) to enhance the biopharmaceutical profile of trastuzumab. Methods: In this study, trastuzumab was linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE) through a peptide linker. Following conjugation, MMAE-trastuzumab ADCs were characterized using SDS-PAGE, UV/VIS, and cell-based ELISA. The inhibitory effects of the ADCs were measured on MDA-MB-453 (HER2-positive cells) and HEK-293 (HER2-negative cells) using in vitro cell cytotoxicity and colony formation assays. Results: Our findings showed that approximately 3.4 MMAE payloads were conjugated to trastuzumab. MMAE-trastuzumab ADCs produced six bands, including H2L2, H2L, HL, H2, H, and L in non-reducing SDS-PAGE. The conjugates exhibited the same binding ability to MDA-MB-453 as unconjugated trastuzumab. The MTT assay showed a significant improvement in the trastuzumab activity following MMAE conjugation, representing a higher antitumor activity as compared with unconjugated trastuzumab. Furthermore, ADCs were capable of potentially inhibiting colony formation in HER2-positive cells, as compared with trastuzumab. Conclusion: MMAE-trastuzumab ADCs represent a promising therapeutic strategy to treat HER2-positive breast cancer.

Item Type: Article
Additional Information: cited By 0
Uncontrolled Keywords: antibody drug conjugate; epidermal growth factor receptor 2; trastuzumab; vedotin, antineoplastic activity; Article; binding affinity; breast cancer; cell viability; colony formation; controlled study; drug cytotoxicity; drug efficacy; drug protein binding; gel filtration chromatography; human; human cell; in vitro study; MTT assay; optical density; polyacrylamide gel electrophoresis; priority journal; protein cleavage
Subjects: QU Biochemistry > Cell biology and genetics
Divisions: Reserach Vice-Chancellar Department > Cellular and Molecular Research Center
Depositing User: zeynab . bagheri
Date Deposited: 07 Jun 2021 09:39
Last Modified: 08 Jun 2021 05:08
URI: http://eprints.skums.ac.ir/id/eprint/9090

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