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Synthesis and Characterization of Cetuximab–Docetaxel and Panitumumab–Docetaxel Antibody–Drug Conjugates for EGFR-Overexpressing Cancer Therapy
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2018-09-18 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00672
Dylan M. Glatt 1 , Denis R. Beckford Vera 2 , Shamit S. Prabhu 1 , Russell J. Mumper 1 , J. Christopher Luft 1 , S. Rahima Benhabbour 1, 3 , Matthew C. Parrott 2
Affiliation  

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.

中文翻译:

西妥昔单抗-多西他赛和帕尼单抗-多西他赛抗体-药物的合成和表征可用于EGFR过表达的癌症治疗

抗癌抗体-药物偶联物(ADC)的安全性和功效取决于靶向肿瘤的单克隆抗体(mAb),接头和药物的选择,以及它们的特定化学排列和连接化学。在这项研究中,我们使用异双功能交联剂将多西他赛(DX)与西妥昔单抗(CET)或帕尼单抗(PAN)缀合。研究了所得ADC的体外EGFR特异性细胞毒性和体内抗癌活性。优化了反应条件,例如还原剂,时间,温度和烷基化缓冲液,以产生有效且稳定的ADC,具有一致的批次间药物与抗体的比率(DARs)。ADC的DAR从0.4到3.0合成,修饰后所有ADC都保留了它们的EGFR亲和力和特异性。ADC对细胞表面野生型EGFR表达敏感,与U87MG细胞相比,在表达EGFR的A431和MDA-MB-231细胞系中表现出更大的细胞毒性。与使用1 mg / kg DX的相同治疗方案相比,每周以100 mg / kg西妥昔单抗–多西他赛ADC(C-SC-DX,DAR 2.5)治疗的A431荷瘤小鼠表现出持久的抗癌反应,并改善了总体存活率,每周一次,连续四个星期,100 mg / kg CET或1 mg / kg DX和100 mg / kg CET的组合。
更新日期:2018-09-18
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