Pyrrolobenzodiazepine Dimer Antibody-Drug Conjugates: Synthesis and Evaluation of Noncleavable Drug-Linkers
Pyrrolobenzodiazepine Dimer Antibody-Drug Conjugates: Synthesis and Evaluation of Noncleavable Drug-Linkers
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DOI：
10.1021/acs.jmedchem.7b00736
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发表时间：
2017-12-14
影响因子：
7.3
通讯作者：
Howard, Philip W.
中科院分区：
文献类型：
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作者：
Gregson, Stephen J.;Masterson, Luke A.;Howard, Philip W.
通过中间体19合成了三种合理设计的吡咯苯二氮卓类药物连接物，用于抗体药物偶联物（adc）。它们在连接体中缺乏可切割的触发器，由用于半胱氨酸抗体偶联的马来酰亚胺、亲水性间隔物以及与PBD连接的炔(6)、三唑(7)或哌嗪(8)组成。抗HER2 adc （HER2 0 MCF7，均失活）的HER2 3+ SK-BR-3和KPL-4（7失活）的体外IC50值为11-48 ng/mL；抗CD22 adc （CD22 0 Jurkat，均低剂量失活）的CD22 3+ BJAB和WSU-DLCL2的体外IC50值为0.10-1.73 μ g/mL（7失活）。方正5中抗her2 adc的体内抗肿瘤效果分别为0.5-1 mg/kg、1 mg/kg和3-6 mg/kg，分别为6、8和7。WSU-DLCL2中抗cd22 - 6在2 mg/kg时出现肿瘤停滞。总之，不可切割的pbd - adc表现出强大的活性，特别是在HER2模型中。
Three rationally designed pyrrolobenzodiazepine (PBD) drug-linkers have been synthesized via intermediate 19 for use in antibody drug conjugates (ADCs). They lack a cleavable trigger in the linker and consist of a maleimide for cysteine antibody conjugation, a hydrophilic spacer, and either an alkyne (6), triazole (7), or piperazine (8) link to the PBD. In vitro IC50 values were 11-48 ng/mL in HER2 3+ SK-BR-3 and KPL-4 (7 inactive) for the anti-HER2 ADCs (HER2 0 MCF7, all inactive) and 0.10-1.73 mu g/mL (7 inactive) in CD22 3+ BJAB and WSU-DLCL2 for anti-CD22 ADCs (CD22 0 Jurkat, all inactive at low doses). In-vivo antitumor efficacy for the anti-HER2 ADCs in Founder 5 was observed with tumor stasis at 0.5-1 mg/kg, 1 mg/kg, and 3-6 mg/kg for 6, 8, and 7, respectively. Tumor stasis at 2 mg/kg was observed for anti-CD22 6 in WSU-DLCL2. In summary, noncleavable PBD-ADCs exhibit potent activity, particularly in HER2 models.