Preclinical studies in rats and squirrel monkeys for safety evaluation of the bivalent anti-human T cell immunotoxin, A-dmDT390–bisFv(UCHT1)
| Autor: | Yu Jen Lee, Seong Kyu Park, Soo Hyun Kang, Tony Dang, Jen Sing Liu, Sarah H. Bour, Jung Hee Woo, Elissa A. Andreas, Arthur E. Frankel, David M. Neville |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Adult
Male Cancer Research Drug-Related Side Effects and Adverse Reactions Maximum Tolerated Dose Recombinant Fusion Proteins T-Lymphocytes CD3 T cell medicine.medical_treatment Immunology Drug Evaluation Preclinical Biology Pharmacology Rats Sprague-Dawley Immune system Immunotoxin medicine Animals Humans Immunology and Allergy Saimiri Cell Proliferation Diphtheria toxin Dose-Response Relationship Drug Immunotoxins Squirrel monkey Immunotherapy biology.organism_classification Rats medicine.anatomical_structure Oncology Leukocytes Mononuclear biology.protein Female Liver function |
| Zdroj: | Cancer Immunology, Immunotherapy. 57:1225-1239 |
| ISSN: | 1432-0851 0340-7004 |
| DOI: | 10.1007/s00262-008-0457-x |
| Popis: | 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 CD3 epsilon. This immunotoxin selectively kills CD3 epsilon 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 microg/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 CD3 epsilon 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% CD3 epsilon receptor occupancy was 7.4 nM. The MTD of 200 microg/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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink