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

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Summary

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.

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Acknowledgments

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.

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Authors and Affiliations

  1. 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

    Xuhui Bao, Vidyalakshmi Chandramohan, Roger E. McLendon, Michael R. Zalutsky, Chien-Tsun Kuan & Darell D. Bigner

  2. Division of Laboratory Animal Resources, Duke University Medical Center, Durham, NC, USA

    Randall P. Reynolds & John N. Norton

  3. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA

    William C. Wetsel, Ramona M. Rodriguiz, Dipendra K. Aryal & Edward D. Levin

  4. Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, USA

    William C. Wetsel, Ramona M. Rodriguiz & Dipendra K. Aryal

  5. Department of Neurobiology, Duke University Medical Center, Durham, NC, USA

    William C. Wetsel

  6. Department of Cell Biology, Duke University Medical Center, Durham, NC, USA

    William C. Wetsel

  7. Department of Radiology, Duke University Medical Center, Durham, NC, USA

    Neil A. Petry & Michael R. Zalutsky

  8. Duke Translational Medicine Institute, Regulatory Affairs Office, Durham, NC, USA

    Bruce K. Burnett

  9. School of Medicine, Duke University, Durham, NC, USA

    Bruce K. Burnett

  10. Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Ira H. Pastan

Authors
  1. Xuhui Bao
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  2. Vidyalakshmi Chandramohan
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  3. Randall P. Reynolds
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  4. John N. Norton
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  5. William C. Wetsel
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  7. Dipendra K. Aryal
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  8. Roger E. McLendon
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  9. Edward D. Levin
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  10. Neil A. Petry
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  11. Michael R. Zalutsky
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  12. Bruce K. Burnett
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  13. Chien-Tsun Kuan
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  14. Ira H. Pastan
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  15. Darell D. Bigner
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Correspondence to Darell D. Bigner.

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Bao, X., Chandramohan, V., Reynolds, R.P. et al. Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats. Invest New Drugs 34, 149–158 (2016). https://doi.org/10.1007/s10637-015-0318-3

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