title: Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats.
abstract: D2C7-(scdsFv)-PE38KDEL (D2C7-IT) is a novel immunotoxin that reacts with wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFRvIII proteins overexpressed in glioblastomas. This study assessed the toxicity of intracerebral administration of D2C7-IT to support an initial Food and Drug Administration Investigational New Drug application. After the optimization of the formulation and administration, two cohorts (an acute and chronic cohort necropsied on study days 5 and 34) of Sprague-Dawley (SD) rats (four groups of 5 males and 5 females) were infused with the D2C7-IT formulation at total doses of 0, 0.05, 0.1, 0.4 μg (the acute cohort) and 0, 0.05, 0.1, 0.35 μg (the chronic cohort) for approximately 72 h by intracerebral convection-enhanced delivery using osmotic pumps. Mortality was observed in the 0.40 μg (5/10 rats) and 0.35 μg (4/10 rats) high-dose groups of each cohort. Body weight loss and abnormal behavior were only revealed in the rats treated with high doses of D2C7-IT. No dose-related effects were observed in clinical laboratory tests in either cohort. A gross pathologic examination of systemic tissues from the high-dose and control groups in both cohorts exhibited no dose-related or drug-related pathologic findings. Brain histopathology revealed the frequent occurrence of dose-related encephalomalacia, edema, and demyelination in the high-dose groups of both cohorts. In this study, the maximum tolerated dose of D2C7-IT was determined to be between 0.10 and 0.35 μg, and the no-observed-adverse-effect-level was 0.05 μg in SD rats. Both parameters were utilized to design the Phase I/II D2C7-IT clinical trial.
authors.affiliation: Preston Robert Tisch Brain Tumor Center at Duke and Department of Pathology, Duke University Medical Center, 177 MSRB-1, 203 Research Drive, Box 3156, Durham, NC, USA.
authors.forename: Xuhui
authors.initials: X
authors.lastname: Bao
authors.affiliation: Preston Robert Tisch Brain Tumor Center at Duke and Department of Pathology, Duke University Medical Center, 177 MSRB-1, 203 Research Drive, Box 3156, Durham, NC, USA.
authors.forename: Vidyalakshmi
authors.initials: V
authors.lastname: Chandramohan
authors.affiliation: Division of Laboratory Animal Resources, Duke University Medical Center, Durham, NC, USA.
authors.forename: Randall P
authors.initials: RP
authors.lastname: Reynolds
authors.affiliation: Division of Laboratory Animal Resources, Duke University Medical Center, Durham, NC, USA.
authors.forename: John N
authors.initials: JN
authors.lastname: Norton
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.|Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, USA.|Department of Neurobiology, Duke University Medical Center, Durham, NC, USA.|Department of Cell Biology, Duke University Medical Center, Durham, NC, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.|Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, USA.
authors.forename: Ramona M
authors.initials: RM
authors.lastname: Rodriguiz
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.|Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, USA.
authors.forename: Dipendra K
authors.initials: DK
authors.lastname: Aryal
authors.affiliation: Preston Robert Tisch Brain Tumor Center at Duke and Department of Pathology, Duke University Medical Center, 177 MSRB-1, 203 Research Drive, Box 3156, Durham, NC, USA.
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Levin
authors.affiliation: Department of Radiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Petry
authors.affiliation: Preston Robert Tisch Brain Tumor Center at Duke and Department of Pathology, Duke University Medical Center, 177 MSRB-1, 203 Research Drive, Box 3156, Durham, NC, USA.|Department of Radiology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zalutsky
authors.affiliation: Duke Translational Medicine Institute, Regulatory Affairs Office, Durham, NC, USA.|School of Medicine, Duke University, Durham, NC, USA.
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Burnett
authors.affiliation: Preston Robert Tisch Brain Tumor Center at Duke and Department of Pathology, Duke University Medical Center, 177 MSRB-1, 203 Research Drive, Box 3156, Durham, NC, USA.
authors.forename: Chien-Tsun
authors.initials: CT
authors.lastname: Kuan
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ira H
authors.initials: IH
authors.lastname: Pastan
authors.affiliation: Preston Robert Tisch Brain Tumor Center at Duke and Department of Pathology, Duke University Medical Center, 177 MSRB-1, 203 Research Drive, Box 3156, Durham, NC, USA. darell.bigner@duke.edu.
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D018481:Convection; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D005260:Female; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000633:toxicity*; D000922:Immunotoxins / Q000008:administration & dosage* / Q000633:toxicity*; D020128:Inhibitory Concentration 50; D007276:Injections, Intraventricular; D008297:Male; D017207:Rats, Sprague-Dawley; D057127:Single-Chain Antibodies / Q000008:administration & dosage* / Q000633:toxicity*
chemical_list: C000612646:D2C7-(scdsFv)-PE38KDEL; D018796:Immunoconjugates; D000922:Immunotoxins; D057127:Single-Chain Antibodies
keywords: Convection-enhanced delivery; D2C7-(scdsFv)-PE38KDEL; Immunotoxin; Rat; Toxicity