Document Type : Original Article
Authors
- Jafar Mahmoudian 1, 2
- Roya Ghods 3, 4
- Mahmood Jeddi-Tehrani 2
- Nassim Ghaffari-Tabrizi-Wizsy 5
- Mohammad Reza Nejadmoghaddam 6
- Ramin Ghahremanzadeh 6
- Seyed Nasser Ostad 1, 7
- Amir-Hassan Zarnani 8, 9
1 Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran.
2 Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran.
3 Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran.
4 Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.
5 SFL Chicken CAM Lab, Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, 8010, Austria.
6 Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran.
7 Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
8 Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
9 Reproductive Immunology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran.
Abstract
Background: Placenta-specific 1 (PLAC1) is one of the oncoplacental genes ectopically expressed in various cancers. Antibody-drug conjugates (ADC) have the potential to substantially improve efficacy and reduce toxicity of treatment compared with cytotoxic small-molecule drugs. They have recently been employed to treat cancers.
Objective: To examine the efficacy of an SN38-conjugated monoclonal anti-PLAC1 antibody in breast cancer.
Methods: Anti-human PLAC1 monoclonal antibodies were produced and characterized. SN38 was conjugated to an anti-PLAC1 antibody (clone: 2H12C12) and conjugation efficacy was evaluated by UV spectrophotometry. Post-conjugation reactivity was then tested using ELISA and flow cytometry. In vitro, cytotoxicity profiling of 2H12C12-SN38 was examined on MDA-MB-231 breast cancer cells using a fluorimetric assay. The effect of 2H12C12-SN38 on MDA-MB-231 tumor growth and angiogenesis ex vivo was tested by chorioallantoic membrane (CAM) assay followed by immunohistochemical analysis of the tumor. Pharmacokinetics of 2H12C12-SN38 in mice was measured by successive venipuncture after ADC administration. Inhibitory effects of anti-PLAC1 ADC on tumor growth were assessed in a nude mice xenograft model of human breast cancer.
Results: Anti-PLAC1 ADC exerted a substantial cytotoxicity on MDA-MB-231 cells starting from a concentration of about 33 nM. ADC also significantly decreased the growth of MDA-MB-231 tumors on CAM assay but did not show a significant effect on tumor angiogenesis. Pharmacokinetics of anti-PLAC1 ADC in mice showed an average half-life (t1/2) of about 80 hours.
Conclusion: Treatment of nude mice with ADC resulted in a significant decrease in tumor size compared to isotype-matched antibody-SN38 conjugate, unconjugated anti-PLAC1 antibody, or free SN38.
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