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. Neville, Arthur E. Frankel

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1225-1239
Number of pages15
JournalCancer Immunology, Immunotherapy
Volume57
Issue number8
DOIs
StatePublished - Aug 2008

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Immunotoxins
Saimiri
T-Lymphocytes
Safety
Maximum Tolerated Dose
Cytokines
Diphtheria Toxin
Neoplasms
Lethargy
Liver
Transaminases
Thomsen-Friedenreich antibodies
Half-Life
Weight Loss
Rodentia
Catalytic Domain
Pharmacokinetics
Kidney
Pharmaceutical Preparations

Keywords

  • CD3 positive
  • Diphtheria toxin
  • MTD
  • UCHT1

ASJC Scopus subject areas

  • Cancer Research
  • Immunology
  • Oncology

Cite this

Preclinical studies in rats and squirrel monkeys for safety evaluation of the bivalent anti-human T cell immunotoxin, A-dmDT390-bisFv(UCHT1). / Woo, Jung Hee; Bour, Sarah H.; Dang, Tony; Lee, Yu Jen; Park, Seong Kyu; Andreas, Elissa; Kang, Soo Hyun; Liu, Jen Sing; Neville, David M.; Frankel, Arthur E.

In: Cancer Immunology, Immunotherapy, Vol. 57, No. 8, 08.2008, p. 1225-1239.

Research output: Contribution to journalArticle

Woo, Jung Hee ; Bour, Sarah H. ; Dang, Tony ; Lee, Yu Jen ; Park, Seong Kyu ; Andreas, Elissa ; Kang, Soo Hyun ; Liu, Jen Sing ; Neville, David M. ; Frankel, Arthur E. / Preclinical studies in rats and squirrel monkeys for safety evaluation of the bivalent anti-human T cell immunotoxin, A-dmDT390-bisFv(UCHT1). In: Cancer Immunology, Immunotherapy. 2008 ; Vol. 57, No. 8. pp. 1225-1239.
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