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Synthesis and Characterization of Cetuximab-Docetaxel and Panitumumab-Docetaxel Antibody-Drug Conjugates for EGFR-Overexpressing Cancer Therapy.
- Source :
-
Molecular pharmaceutics [Mol Pharm] 2018 Nov 05; Vol. 15 (11), pp. 5089-5102. Date of Electronic Publication: 2018 Oct 01. - Publication Year :
- 2018
-
Abstract
- 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.
- Subjects :
- Animals
Antineoplastic Combined Chemotherapy Protocols chemistry
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Cell Line, Tumor
Cetuximab chemistry
Cetuximab pharmacology
Cetuximab therapeutic use
Cross-Linking Reagents chemistry
Docetaxel chemistry
Docetaxel pharmacology
Docetaxel therapeutic use
ErbB Receptors antagonists & inhibitors
ErbB Receptors immunology
ErbB Receptors metabolism
Humans
Immunoconjugates chemistry
Immunoconjugates therapeutic use
Mice
Mice, Nude
Neoplasms mortality
Neoplasms pathology
Panitumumab chemistry
Panitumumab pharmacology
Panitumumab therapeutic use
Survival Analysis
Tissue Distribution
Treatment Outcome
Xenograft Model Antitumor Assays
Antineoplastic Combined Chemotherapy Protocols pharmacology
Immunoconjugates pharmacology
Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1543-8392
- Volume :
- 15
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Molecular pharmaceutics
- Publication Type :
- Academic Journal
- Accession number :
- 30226780
- Full Text :
- https://doi.org/10.1021/acs.molpharmaceut.8b00672