Staquicini D I, D'Angelo S, Ferrara F, Karjalainen K, Sharma G, Smith T L, Tarleton C A, Jaalouk D E, Kuniyasu A, Baze W B, Chaffee B K, Hanley P W, Barnhart K F, Koivunen E, Marchiò S, Sidman R L, Cortes J E, Kantarjian H M, Arap W, Pasqualini R
University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA.
Department of Internal Medicine, Division of Molecular Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA.
Pharmacogenomics J. 2018 May 22;18(3):436-443. doi: 10.1038/tpj.2017.46. Epub 2017 Dec 5.
Translation of drug candidates into clinical settings requires demonstration of preclinical efficacy and formal toxicology analysis for filling an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA). Here, we investigate the membrane-associated glucose response protein 78 (GRP78) as a therapeutic target in leukemia and lymphoma. We evaluated the efficacy of the GRP78-targeted proapoptotic drug bone metastasis targeting peptidomimetic 78 (BMTP-78), a member of the D(KLAKLAK)2-containing class of agents. BMTP-78 was validated in cells from patients with acute myeloid leukemia and in a panel of human leukemia and lymphoma cell lines, where it induced dose-dependent cytotoxicity in all samples tested. Based on the in vitro efficacy of BMTP-78, we performed formal good laboratory practice toxicology studies in both rodents (mice and rats) and nonhuman primates (cynomolgus and rhesus monkeys). These analyses represent required steps towards an IND application of BMTP-78 for theranostic first-in-human clinical trials.
将候选药物转化为临床应用需要证明临床前疗效并进行正式的毒理学分析，以便向美国食品药品监督管理局（FDA）提交新药临床试验申请（IND）。在此，我们研究膜相关葡萄糖反应蛋白78（GRP78）作为白血病和淋巴瘤的治疗靶点。我们评估了靶向GRP78的促凋亡药物骨转移靶向拟肽78（BMTP-78）的疗效，它是含D(KLAKLAK)2类药物的一员。BMTP-78在急性髓系白血病患者的细胞以及一组人类白血病和淋巴瘤细胞系中得到验证，在所有测试样本中它都能诱导剂量依赖性细胞毒性。基于BMTP-78的体外疗效，我们在啮齿动物（小鼠和大鼠）和非人类灵长类动物（食蟹猴和恒河猴）中进行了正式的良好实验室规范毒理学研究。这些分析是BMTP-78用于治疗诊断性首次人体临床试验的IND申请所需的步骤。
