Placenta-specific1 (PLAC1) is a potential target for antibody-drug conjugate-based prostate cancer immunotherapy.
Placenta-specific1 (PLAC1) is a potential target for antibody-drug conjugate-based prostate cancer immunotherapy.
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DOI：
10.1038/s41598-017-13682-9
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发表时间：
2017-10-17
影响因子：
4.6
通讯作者：
Dinarvand R
中科院分区：
文献类型：
--
作者：
Nejadmoghaddam MR;Zarnani AH;Ghahremanzadeh R;Ghods R;Mahmoudian J;Yousefi M;Nazari M;Ghahremani MH;Abolhasani M;Anissian A;Mahmoudi M;Dinarvand R
我们最近的研究结果强烈支持PLAC 1作为前列腺癌（PCa）潜在免疫靶点的想法。在这里，我们已经产生并评估了一种基于抗胎盘特异性1（PLAC 1）的抗体药物偶联物（ADC），用于PCa的靶向免疫治疗。前列腺癌细胞表达相当水平的PLAC 1。抗PLAC 1克隆2 H12 C12在前列腺癌细胞中显示出与重组PLAC 1的高反应性和选择性识别PLAC 1，但在阴性对照LS 180细胞中不显示。PLAC 1结合在几分钟内诱导抗体的快速内化，其在15分钟后达到约50%，并且几乎在1小时内完成。在SN 38与抗体缀合后，实现了约5.5的药物-抗体比（DAR），而对抗体与细胞表面抗原的亲和力没有明显的负面影响。ADC保留了固有的抗体活性，并显示出增强的选择性细胞毒性，IC 50为62 nM，比游离药物低约15倍。抗PLAC 1-ADC诱导人原发性前列腺癌细胞和前列腺细胞系的凋亡。在体内动物安全性实验中未观察到明显的细胞毒性作用。我们新开发的基于抗PLAC 1的ADC可能为PCa患者提供可靠，有效和新颖的免疫治疗方式铺平道路。
Our recent findings strongly support the idea of PLAC1 being as a potential immunotherapeutic target in prostate cancer (PCa). Here, we have generated and evaluated an anti-placenta-specific1 (PLAC1)-based antibody drug conjugate (ADC) for targeted immunotherapy of PCa. Prostate cancer cells express considerable levels of PLAC1. The Anti-PLAC1 clone, 2H12C12, showed high reactivity with recombinant PLAC1 and selectivity recognized PLAC1 in prostate cancer cells but not in LS180 cells, the negative control. PLAC1 binding induced rapid internalization of the antibody within a few minutes which reached to about 50% after 15 min and almost completed within an hour. After SN38 conjugation to antibody, a drug-antibody ratio (DAR) of about 5.5 was achieved without apparent negative effect on antibody affinity to cell surface antigen. The ADC retained intrinsic antibody activity and showed enhanced and selective cytotoxicity with an IC50 of 62 nM which was about 15-fold lower compared to free drug. Anti-PLAC1-ADC induced apoptosis in human primary prostate cancer cells and prostate cell lines. No apparent cytotoxic effect was observed in in vivo animal safety experiments. Our newly developed anti-PLAC1-based ADCs might pave the way for a reliable, efficient, and novel immunotherapeutic modality for patients with PCa.
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影响因子：
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作者：
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通讯作者：
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