Therapeutic targeting of membrane-associated GRP78 in leukemia and lymphoma: Preclinical efficacy in vitro and formal toxicity study of BMTP-78 in rodents and primates
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Nature Publishing Group
Abstract
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. © 2018 Macmillan Publishers Limited, part of Springer Nature.
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Animals, Cell line, tumor, Cell survival, Drug evaluation, preclinical, Heat-shock proteins, Humans, Leukemia, Lymphoma, Macaca fascicularis, Macaca mulatta, Mice, Molecular targeted therapy, Peptidomimetics, Primates, Rats, United states, United states food and drug administration, Antineoplastic agent, Bmtp 78, Glucose regulated protein 78, Peptidomimetic agent, Unclassified drug, Heat shock protein, Molecular chaperone grp78, Acute myeloid leukemia, Animal cell, Animal experiment, Animal model, Animal tissue, Article, Cardiotoxicity, Controlled study, Cytotoxicity, Dose response, Drug efficacy, Drug screening, Drug targeting, Female, Good laboratory practice, Human, Human cell, Human tissue, In vitro study, Inflammation, Injection site reaction, Kidney injury, Leukemia cell line, Lymphoma cell line, Male, Mouse, Necrosis, Nephrotoxicity, Nonhuman, Preclinical study, Priority journal, Rat, Rhesus monkey, Toxicity testing, Tumor growth, Animal, Antagonists and inhibitors, Drug effect, Food and drug administration, Genetics, Molecularly targeted therapy, Pathology, Primate, Tumor cell line