Toxicology and pharmacokinetics of DT388IL3, a fusion toxin consisting of a truncated diphtheria toxin (DT388) linked to human interleukin 3 (IL3), in cynomolgus monkeys

被引:27
作者
Cohen, KA
Liu, TF
Cline, JM
Wagner, JD
Hall, PD
Frankel, AE
机构
[1] Wake Forest Hlth Sci, Dept Comparat Med & Canc Biol, Winston Salem, NC 27157 USA
[2] Med Univ S Carolina, Coll Pharm, Charleston, SC 29425 USA
关键词
diphtheria toxin; fusion toxin; acute myeloid leukemia; DT(388)IL3;
D O I
10.1080/10428190410001663572
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The fusion toxin DT388 IL3 composed of the catalytic and translocation domains of diphtheria toxin (DT388) linked to interleukin-3 (IL3) was administered to 6 cynomolgus monkeys which possessed cross-reactive IL3 receptors. Groups of 2 animals (1 male and 1 female) received up to 6 every other day slow intravenous infusions of 40, 60, or 100 mug/kg DT388 IL3. Monkeys given 40 or 60 mug/kg showed mild or moderate transient malaise and anorexia, respectively, without evidence of organ damage by blood tests or histopathology. Animals treated at 100 mug/kg showed severe malaise and anorexia. The female monkey had moderate to severe vasculitis in multiple tissues. Necropsies were performed on the 40 mug/kg monkeys on day 14 and the 100 mug/kg monkeys on days 6 and 7. DT388 IL3 plasma half-life was similar to30 min with a peak concentration of 0.45 mug/ml or 10,000 pM (IC50 for AML blasts treated in vitro was 6 pM). Immune responses were minimal in 4 animals tested at 12 days and 2 animals tested at 30 days post treatment with anti-DT388 IL3 levels < 1 mug/ml. Bone marrow aspirates were obtained on all animals at day 19 or at necropsy and revealed myeloid suppression in the females and myeloid hyperplasia in the males irrespective of dose groups. The maximal tolerated dose of 60 mug/kg for 6 doses is markedly higher than other recombinant diphtheria toxins and provides a dose level sufficient for anti-leukemic activity in vitro and in rodent models. Thus, we propose this agent is a promising drug for AML patients.
引用
收藏
页码:1647 / 1656
页数:10
相关论文
共 31 条
[21]  
MAYER P, 1989, BLOOD, V74, P613
[22]   Acute myeloid leukemia in adults: where do we go from here? [J].
Schiffer, CA .
CANCER CHEMOTHERAPY AND PHARMACOLOGY, 2001, 48 (Suppl 1) :S45-S52
[23]  
SILVERMAN JA, 1994, J BIOL CHEM, V269, P22524
[24]   PERMISSIVE ROLE OF INTERLEUKIN-3 (IL-3) IN PROLIFERATION AND DIFFERENTIATION OF MULTIPOTENTIAL HEMATOPOIETIC PROGENITORS IN CULTURE [J].
SUDA, T ;
SUDA, J ;
OGAWA, M ;
IHLE, JN .
JOURNAL OF CELLULAR PHYSIOLOGY, 1985, 124 (02) :182-190
[25]   New developments in antibody therapy for acute myeloid leukemia [J].
Tomblyn, MR ;
Tallman, MS .
SEMINARS IN ONCOLOGY, 2003, 30 (04) :502-508
[26]  
Uckun FM, 1997, CLIN CANCER RES, V3, P325
[27]   Targeting myeloid leukemia with a DT390-mIL-3 fusion immunotoxin:: ex vivo and in vivo studies in mice [J].
Vallera, DA ;
Seo, SY ;
Panoskaltsis-Mortari, A ;
Griffin, JD ;
Blazar, BR .
PROTEIN ENGINEERING, 1999, 12 (09) :779-785
[28]   Fusion protein toxins based on diphtheria toxin: Selective targeting of growth factor receptors of eukaryotic cells [J].
vanderSpek, JC ;
Murphy, JR .
APPLICATIONS OF CHIMERIC GENES AND HYBRID PROTEINS PT B, 2000, 327 :239-249
[29]  
VANGILS FCJM, 1993, AM J PATHOL, V143, P1621
[30]  
VANGILS FCJM, 1994, EXP HEMATOL, V22, P248