Synthesis and Characterization of Cetuximab–Docetaxel and Panitumumab–Docetaxel Antibody–Drug Conjugates for EGFR-Overexpressing Cancer Therapy
| Autor: | Russell J. Mumper, S. Rahima Benhabbour, Shamit S. Prabhu, Matthew C. Parrott, Denis R. Beckford Vera, J. Christopher Luft, Dylan M. Glatt |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Antibody-drug conjugate Immunoconjugates medicine.drug_class Cetuximab Mice Nude Pharmaceutical Science Docetaxel Monoclonal antibody Mice 03 medical and health sciences 0302 clinical medicine In vivo Cell Line Tumor Neoplasms Antineoplastic Combined Chemotherapy Protocols Drug Discovery medicine Animals Humans Panitumumab Tissue Distribution Cytotoxicity Chemistry Survival Analysis Xenograft Model Antitumor Assays ErbB Receptors body regions Cross-Linking Reagents Treatment Outcome 030104 developmental biology 030220 oncology & carcinogenesis Cancer research Molecular Medicine Conjugate medicine.drug |
| Zdroj: | Molecular Pharmaceutics. 15:5089-5102 |
| ISSN: | 1543-8392 1543-8384 |
| DOI: | 10.1021/acs.molpharmaceut.8b00672 |
| Popis: | The safety and efficacy of anticancer antibody-drug conjugates (ADCs) depend on the selection of tumor-targeting monoclonal antibody (mAb), linker, and drug, as well as their specific chemical arrangement and linkage chemistry. In this study, we used a heterobifunctional cross-linker to conjugate docetaxel (DX) to cetuximab (CET) or panitumumab (PAN). The resulting ADCs were investigated for their in vitro EGFR-specific cytotoxicity and in vivo anticancer activity. Reaction conditions, such as reducing agent, time, temperature, and alkylation buffer, were optimized to yield potent and stable ADCs with consistent batch-to-batch drug-to-antibody ratios (DARs). ADCs were synthesized with DARs from 0.4 to 3.0, and all retained their EGFR affinity and specificity after modification. ADCs were sensitive to cell surface wildtype EGFR expression, demonstrating more cytotoxicity in EGFR-expressing A431 and MDA-MB-231 cell lines compared to U87MG cells. A431 tumor-bearing mice treated once weekly for four weeks with 100 mg/kg cetuximab-docetaxel ADC (C-SC-DX, DAR 2.5) showed durable anticancer responses and improved overall survival compared to the same treatment regimen with 1 mg/kg DX, 100 mg/kg CET, or a combination 1 mg/kg DX and 100 mg/kg CET. New treatment options are emerging for patients with both wild-type and mutated EGFR-overexpressing cancers, and these studies highlight the potential role of EGFR-targeted ADC therapies as a promising new treatment option. |
| Databáze: | OpenAIRE |
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