Investigational New Drugs

, Volume 34, Issue 2, pp 149–158 | Cite as

Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats

  • Xuhui Bao
  • Vidyalakshmi Chandramohan
  • Randall P. Reynolds
  • John N. Norton
  • William C. Wetsel
  • Ramona M. Rodriguiz
  • Dipendra K. Aryal
  • Roger E. McLendon
  • Edward D. Levin
  • Neil A. Petry
  • Michael R. Zalutsky
  • Bruce K. Burnett
  • Chien-Tsun Kuan
  • Ira H. Pastan
  • Darell D. BignerEmail author


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.


D2C7-(scdsFv)-PE38KDEL Immunotoxin Convection-enhanced delivery Toxicity Rat 



We thank Terri Lucas and Lena Perdue for coordinating the study, Charles Pegram, David Soule, and Xiao-Guang Zhao for the formulation preparation, and Colleen Herbst, Meredith Weksler, and Fernando Orozco for their surgical assistance. We wish to thank Christopher Means and Theo Rhodes for their detailed assessment of the animals for the Functional Observation Battery (FOB) and assistance in preparing and analyzing the FOB data. We also thank Jenna Lewis for her editorial assistance. The study was funded by the following grant from the National Institutes of Health (NIH) of the United States: P01-CA154291-03 (to D.D. Bigner). This research was also supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

Compliance with ethical standards

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Supplementary material

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Xuhui Bao
    • 1
  • Vidyalakshmi Chandramohan
    • 1
  • Randall P. Reynolds
    • 2
  • John N. Norton
    • 2
  • William C. Wetsel
    • 3
    • 4
    • 5
    • 6
  • Ramona M. Rodriguiz
    • 3
    • 4
  • Dipendra K. Aryal
    • 3
    • 4
  • Roger E. McLendon
    • 1
  • Edward D. Levin
    • 3
  • Neil A. Petry
    • 7
  • Michael R. Zalutsky
    • 1
    • 7
  • Bruce K. Burnett
    • 8
    • 9
  • Chien-Tsun Kuan
    • 1
  • Ira H. Pastan
    • 10
  • Darell D. Bigner
    • 1
    Email author
  1. 1.Preston Robert Tisch Brain Tumor Center at Duke and Department of PathologyDuke University Medical CenterDurhamUSA
  2. 2.Division of Laboratory Animal ResourcesDuke University Medical CenterDurhamUSA
  3. 3.Department of Psychiatry and Behavioral SciencesDuke University Medical CenterDurhamUSA
  4. 4.Mouse Behavioral and Neuroendocrine Analysis Core FacilityDuke University Medical CenterDurhamUSA
  5. 5.Department of NeurobiologyDuke University Medical CenterDurhamUSA
  6. 6.Department of Cell BiologyDuke University Medical CenterDurhamUSA
  7. 7.Department of RadiologyDuke University Medical CenterDurhamUSA
  8. 8.Duke Translational Medicine InstituteRegulatory Affairs OfficeDurhamUSA
  9. 9.School of MedicineDuke UniversityDurhamUSA
  10. 10.Laboratory of Molecular Biology, Center for Cancer ResearchNational Cancer Institute, National Institutes of HealthBethesdaUSA

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