2. Academic Validation
  3. Development and biological assessment of MMAE-trastuzumab antibody-drug conjugates (ADCs)

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

  • Breast Cancer. 2021 Jan;28(1):216-225. doi: 10.1007/s12282-020-01153-5.
Sajad Yaghoubi 1,  Tohid Gharibi 2 3,  Mohammad Hossein Karimi 4,  Muhammad Sadeqi Nezhad 5 6,  Alexander Seifalian 7,  Reza Tavakkol 8,  Nader Bagheri 9,  Asiyeh Dezhkam 10,  Meghdad Abdollahpour-Alitappeh 11
Affiliations

Affiliations

  • 1 Department of Clinical Microbiology, Iranshahr University of Medical Sciences, Iranshahr, Iran.
  • 2 Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
  • 3 Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
  • 4 Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
  • 5 Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Gorgan, Iran.
  • 6 Stem Cells and Regenerative Medicine Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran.
  • 7 Nanotechnology and Regenerative Medicine Commercialization Centre (Ltd), The London BioScience Innovation Centre, London, UK.
  • 8 Department of Nursing, School of Nursing, Larestan University of Medical Sciences, Larestan, Iran.
  • 9 Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.
  • 10 Department of Midwifery, School of Nursing and Midwifery, Iranshahr University of Medical Sciences, Iranshahr, Iran.
  • 11 Cellular and Molecular Biology Research Center, Larestan University of Medical Sciences, Larestan, Iran. Abdollahpour1983@yahoo.com.
PMID: 32889587 DOI: 10.1007/s12282-020-01153-5
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.

Keywords

Antibody drug conjugate (ADC); Breast cancer; Human epidermal growth factor receptor 2 (HER2); MMAE-trastuzumab; Targeted therapy.

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