TY - JOUR
T1 - Preclinical mammalian safety studies of EPHARNA (DOPC Nanoliposomal EphA2-Targeted siRNA)
AU - Wagner, Michael J.
AU - Mitra, Rahul
AU - Mcarthur, Mark J.
AU - Baze, Wallace
AU - Barnhart, Kirstin
AU - Wu, Sherry Y.
AU - Rodriguez-Aguayo, Cristian
AU - Zhang, Xinna
AU - Coleman, Robert L.
AU - Lopez-Berestein, Gabriel
AU - Sood, Anil K.
N1 - Publisher Copyright:
©2017 American Association for Cancer Research.
PY - 2017/6
Y1 - 2017/6
N2 - To address the need for efficient and biocompatible delivery systems for systemic siRNA delivery, we developed 1,2-Dioleoylsn- Glycero-3-Phosphatidylcholine (DOPC) nanoliposomal EphA2-Targeted therapeutic (EPHARNA). Here, we performed safety studies of EPHARNA in murine and primate models. Single dosing of EPHARNA was tested at 5 concentrations in mice (N 1/4 15 per group) and groups were sacrificed on days 1, 14, and 28 for evaluation of clinical pathology and organ toxicity. Multiple dosing of EPHARNA was tested in mice and Rhesus macaques twice weekly at two dose levels in each model. Possible effects on hematologic parameters, serum chemistry, coagulation, and organ toxicity were assessed. Following single-dose EPHARNA administration to mice, no gross pathologic or dose-related microscopic findings were observed in either the acute (24 hours) or recovery (14 and 28 days) phases. The no-observed-Adverseeffect level (NOAEL) for EPHARNA is considered >225 mg/kg when administered as a single injection intravenously in CD-1 mice. With twice weekly injection, EPHARNA appeared to stimulate a mild to moderate inflammatory response in a dose-related fashion. There appeared to be a mild hemolytic reaction in the female mice. In Rhesus macaques, minimal to moderate infiltration of mononuclear cells was found in some organs including the gastrointestinal tract, heart, and kidney. No differences attributed to EPHARNA were observed. These results demonstrate that EPHARNA is well tolerated at all doses tested. These data, combined with previously published in vivo validation studies, have led to an ongoing first-in-human phase I clinical trial (NCT01591356).
AB - To address the need for efficient and biocompatible delivery systems for systemic siRNA delivery, we developed 1,2-Dioleoylsn- Glycero-3-Phosphatidylcholine (DOPC) nanoliposomal EphA2-Targeted therapeutic (EPHARNA). Here, we performed safety studies of EPHARNA in murine and primate models. Single dosing of EPHARNA was tested at 5 concentrations in mice (N 1/4 15 per group) and groups were sacrificed on days 1, 14, and 28 for evaluation of clinical pathology and organ toxicity. Multiple dosing of EPHARNA was tested in mice and Rhesus macaques twice weekly at two dose levels in each model. Possible effects on hematologic parameters, serum chemistry, coagulation, and organ toxicity were assessed. Following single-dose EPHARNA administration to mice, no gross pathologic or dose-related microscopic findings were observed in either the acute (24 hours) or recovery (14 and 28 days) phases. The no-observed-Adverseeffect level (NOAEL) for EPHARNA is considered >225 mg/kg when administered as a single injection intravenously in CD-1 mice. With twice weekly injection, EPHARNA appeared to stimulate a mild to moderate inflammatory response in a dose-related fashion. There appeared to be a mild hemolytic reaction in the female mice. In Rhesus macaques, minimal to moderate infiltration of mononuclear cells was found in some organs including the gastrointestinal tract, heart, and kidney. No differences attributed to EPHARNA were observed. These results demonstrate that EPHARNA is well tolerated at all doses tested. These data, combined with previously published in vivo validation studies, have led to an ongoing first-in-human phase I clinical trial (NCT01591356).
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U2 - 10.1158/1535-7163.MCT-16-0541
DO - 10.1158/1535-7163.MCT-16-0541
M3 - Article
C2 - 28265009
AN - SCOPUS:85020546379
SN - 1535-7163
VL - 16
SP - 1114
EP - 1123
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 6
ER -