An anti-EGFR x cotinine bispecific antibody complexed with cotinine-conjugated duocarmycin inhibits growth of EGFR-positive cancer cells with KRAS mutations
An anti-EGFR x cotinine bispecific antibody complexed with cotinine-conjugated duocarmycin inhibits growth of EGFR-positive cancer cells with KRAS mutations
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DOI：
10.1038/s12276-018-0096-z
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发表时间：
2018-05-24
影响因子：
12.8
通讯作者：
Chung, Junho
中科院分区：
文献类型：
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作者：
Jin, Junyeong;Park, Gunwoo;Chung, Junho
抗体-药物结合物(ADC)可以选择性地将细胞毒剂输送到肿瘤细胞，并且通常比裸抗体更有效。然而，抗体和细胞毒剂之间的偶联过程的优化和ADC的表征是费时费力的过程。在这里，我们描述了一种新的ADC平台，它使用同时与肿瘤相关抗原结合的四价双特异性抗体和连接到细胞毒剂的半抗原。我们选择可替宁作为半抗原，因为它不存在于生物系统中，而且是惰性的和无毒的。我们制备了抗表皮生长因子受体(EGFR)x可替宁双特异性抗体，并将其与等摩尔可替宁偶联的多卡霉素混合形成ADC。该ADC在体外和体内对带有KRAS突变的EGFR阳性、西妥昔单抗耐药的肺腺癌细胞显示出显著的抗肿瘤活性。
Antibody-drug conjugates (ADCs) can selectively deliver cytotoxic agents to tumor cells and are frequently more potent than naked antibodies. However, optimization of the conjugation process between antibodies and cytotoxic agents and characterization of ADCs are laborious and time-consuming processes. Here, we describe a novel ADC platform using a tetravalent bispecific antibody that simultaneously binds to the tumor-associated antigen and a hapten conjugated to a cytotoxic agent. We selected cotinine as the hapten because it is not present in biological systems and is inert and nontoxic. We prepared an anti-epidermal growth factor receptor (EGFR) x cotinine bispecific antibody and mixed it with an equimolar amount of cotinine-conjugated duocarmycin to form the ADC. This ADC showed significant in vitro and in vivo antitumor activity against EGFR-positive, cetuximab-refractory lung adenocarcinoma cells with KRAS mutations.