Cancer Immunology, Immunotherapy

, Volume 57, Issue 8, pp 1225–1239

Preclinical studies in rats and squirrel monkeys for safety evaluation of the bivalent anti-human T cell immunotoxin, A-dmDT390–bisFv(UCHT1)

  • Jung Hee Woo
  • Sarah H. Bour
  • Tony Dang
  • Yu-Jen Lee
  • Seong Kyu Park
  • Elissa Andreas
  • Soo Hyun Kang
  • Jen-Sing Liu
  • David M. NevilleJr
  • Arthur E. Frankel
Original Article

DOI: 10.1007/s00262-008-0457-x

Cite this article as:
Woo, J.H., Bour, S.H., Dang, T. et al. Cancer Immunol Immunother (2008) 57: 1225. doi:10.1007/s00262-008-0457-x

Abstract

The bivalent anti-human T cell immunotoxin A-dmDT390-bisFv(UCHT1) for treatment of patients with T cell malignancies is a single chain fusion protein composed of the catalytic domain and translocation domains of diphtheria toxin fused to two tandem sFv molecules reactive with human CD3ε. This immunotoxin selectively kills CD3ε positive T cells. To determine the maximum tolerated dose (MTD), pharmacokinetics and immunogenicity of A-dmDT390-bisFv(UCHT1), rat and squirrel monkey studies were performed. In both animal studies, animals received either 0, 2.5 (low), 25 (medium), or 56.25 μg/kg (high) of A-dmDT390-bisFv(UCHT1) intravenously twice daily for four consecutive days. Although transient elevation of liver transaminases in the high groups was observed, the A-dmDT390-bisFv(UCHT1) administration did not affect liver function, renal function, the hemogram, or produce serious organ histopathology. Adverse events included transient lethargy, inappetence and weight loss in high groups. A-dmDT390-bisFv(UCHT1) plasma half life was 26.95 min in rats and 18.33 min in squirrel monkeys. Immune responses to A-dmDT390-bisFv(UCHT1) were minimal in squirrel monkeys and mild in rats. In vitro cytokine release, T cell activation and CD3ε receptor occupancy assays using human PBMC were further performed since rat and squirrel monkey T cells do not react with A-dmDT390-bisFv(UCHT1). A-dmDT390-bisFv(UCHT1) did not induce cytokine release or T cell activation. The A-dmDT390-bisFv(UCHT1) concentration for 50% CD3ε receptor occupancy was 7.4 nM. The MTD of 200 μg/kg total provides a dose level sufficient for anti-tumor activity in vitro and in a rodent model. Therefore, we propose that this agent is a promising drug for patients with surface CD3+ T cell malignancies.

Keywords

MTD Diphtheria toxin UCHT1 CD3 positive 

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Jung Hee Woo
    • 1
  • Sarah H. Bour
    • 1
  • Tony Dang
    • 1
    • 3
  • Yu-Jen Lee
    • 1
  • Seong Kyu Park
    • 1
  • Elissa Andreas
    • 1
  • Soo Hyun Kang
    • 1
  • Jen-Sing Liu
    • 1
  • David M. NevilleJr
    • 2
  • Arthur E. Frankel
    • 1
  1. 1.Scott and White Cancer Research InstituteTempleUSA
  2. 2.Biophysical Chemistry Section, Laboratory of Molecular BiologyNational Institute of Mental HealthBethesdaUSA
  3. 3.Global Biologics Supply Chain, Division of Centocor, Inc.RaritanUSA

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