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

Publication ,  Journal Article
Bao, X; Chandramohan, V; Reynolds, RP; Norton, JN; Wetsel, WC; Rodriguiz, RM; Aryal, DK; McLendon, RE; Levin, ED; Petry, NA; Zalutsky, MR ...
Published in: Invest New Drugs
April 2016

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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Published In

Invest New Drugs

DOI

EISSN

1573-0646

Publication Date

April 2016

Volume

34

Issue

2

Start / End Page

149 / 158

Location

United States

Related Subject Headings

  • Single-Chain Antibodies
  • Rats, Sprague-Dawley
  • Oncology & Carcinogenesis
  • Male
  • Injections, Intraventricular
  • Inhibitory Concentration 50
  • Immunotoxins
  • Immunoconjugates
  • Female
  • Drug Evaluation, Preclinical
 

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Bao, X., Chandramohan, V., Reynolds, R. P., Norton, J. N., Wetsel, W. C., Rodriguiz, R. M., … Bigner, D. D. (2016). Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats. Invest New Drugs, 34(2), 149–158. https://doi.org/10.1007/s10637-015-0318-3
Bao, Xuhui, Vidyalakshmi Chandramohan, Randall P. Reynolds, John N. Norton, William C. Wetsel, Ramona M. Rodriguiz, Dipendra K. Aryal, et al. “Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats.Invest New Drugs 34, no. 2 (April 2016): 149–58. https://doi.org/10.1007/s10637-015-0318-3.
Bao X, Chandramohan V, Reynolds RP, Norton JN, Wetsel WC, Rodriguiz RM, et al. Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats. Invest New Drugs. 2016 Apr;34(2):149–58.
Bao, Xuhui, et al. “Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats.Invest New Drugs, vol. 34, no. 2, Apr. 2016, pp. 149–58. Pubmed, doi:10.1007/s10637-015-0318-3.
Bao X, Chandramohan V, Reynolds RP, Norton JN, Wetsel WC, Rodriguiz RM, Aryal DK, McLendon RE, Levin ED, Petry NA, Zalutsky MR, Burnett BK, Kuan C-T, Pastan IH, Bigner DD. Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats. Invest New Drugs. 2016 Apr;34(2):149–158.
Journal cover image

Published In

Invest New Drugs

DOI

EISSN

1573-0646

Publication Date

April 2016

Volume

34

Issue

2

Start / End Page

149 / 158

Location

United States

Related Subject Headings

  • Single-Chain Antibodies
  • Rats, Sprague-Dawley
  • Oncology & Carcinogenesis
  • Male
  • Injections, Intraventricular
  • Inhibitory Concentration 50
  • Immunotoxins
  • Immunoconjugates
  • Female
  • Drug Evaluation, Preclinical