Novel trastuzumab-DM1 conjugate: Synthesis and bio-evaluation |
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Authors: | Mehri Abedi Reza Ahangari Cohan Fereidoun Mahboudi Mohammad Ali Faramarzi Ramin Fazel Narges Damavandi Mehdi Shafiee Ardestani Fatemeh Davami |
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Institution: | 1. Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran;2. Department of Pilot Nanobiotechnology, New Technologies Research Group, Pasteur Institute of Iran, Tehran, Iran;3. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy & Biotechnology Research Center, Tehran University of Medical Sciences, Tehran, Iran;4. Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran;5. Department of Radiopharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran |
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Abstract: | Antibody-drug conjugates are now of considerable interest and are recommended for the treatment of cancers. Linkers are having a crucial role in potency and efficacy of these drugs. Herein, for the first time, we have used a water-soluble poly-ethylene glycol based linker (succinimidyl-(N-maleimido propionamido)-diethyleneglycol] SM(PEG)2]) for lysine amide coupling of DM1 drug to trastuzumab considering evaluation of the effect of using a hydrophilic linker on physicochemical and biological properties of the resulting conjugate in comparison to the conjugate containing succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) linker, which has a relative hydrophobic nature. The physicochemical properties of synthesized conjugates were investigated in terms of drug to antibody ratio, size variants and free drug quantities. In vitro biological activity of trastuzumab-DM1 conjugates was assessed on breast cancer cell lines expressing different levels of HER2 using binding affinity, antiproliferative, apoptosis, and antibody-dependent cell-mediated cytotoxicity (ADCC) assays. Synthesized conjugate containing hydrophilic linker, showed higher drug to antibody ratio, no aggregated form and higher cellular toxicity in comparison to SMCC bearing conjugate. Binding affinity and ADCC potential of conjugates was not affected upon the usage of hydrophilic linker. In conclusion, application of SM(PEG)2 for coupling of DM1 to trastuzumab enhance desirable characteristics of the resulting conjugate. |
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Keywords: | antibody-drug conjugate hydrophilic linker trastuzumab trastuzumab-DM1 conjugates TSPD2 |
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