Evaluation of long-term toxicity of Ad/hIFN-, an Adenoviral vector encoding the human interferon-gamma gene, in nonhuman primates.
Interferon-gamma(IFN-gamma) plays an important role in the immunomodulation and growth inhibition of many tumor cells, but its clinical application is limited by its systemic toxicity. Ad/hIFN-gamma, a nonreplicating adenoviral vector encoding human IFN-gamma, has been reported to inhibit tumor growth in vitro and in a xenograft model. In this study, the long-term toxicity of Ad/hIFN-gamma was assessed in cynomolgus macaques (Macaca fascicularis). Thirty animals were enrolled into 5 groups, and administered intramuscularly, respectively, Ad/hIFN-gamma (3.3 x 10(10), 3.3 x 10(11), or 3.3 x 10(12) VP/kg), Ad/LacZ (vector control, 3.3 x 10(11) VP/kg), or excipient 3 times per week for 8 weeks, followed by a 4-week recovery period. At 12 weeks all experimental animals appeared generally healthy, and there were no statistically significant differences in body weight, urinalysis, hemogram, blood biochemistry, and electrocardiogram results between the treatment and control groups. No significant toxic effects were noted on macroscopic and microscopic examinations of organs and tissues. Preliminary investigation of the immunotoxicity of Ad/IFN-gamma indicated that anti-adenoviral and anti-hIFN-gamma antibodies were generated. These data demonstrate that long-term, high-dose intramuscular administration of Ad/IFN-gamma was not notably toxic and might be safe for clinical therapeutic use.
Li
Yan
Y
State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou 510060, People's Republic of China.
Shao
Jian-Yong
JY
Liu
Ran-yi
RY
Zhou
Ling
L
Chai
Li-ping
LP
Li
Hong-li
HL
Han
Hong-yu
HY
Huang
Bi-jun
BJ
Zeng
Mu-sheng
MS
Zhu
Xiao-feng
XF
Liu
Qiang
Q
Fu
Li-wu
LW
Huang
Wenlin
W
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D001774:Blood Chemical Analysis; D001835:Body Weight; D004562:Electrocardiography; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000633:toxicity*; D006403:Hematologic Tests; D006652:Histological Techniques; D006801:Humans; D007273:Injections, Intramuscular; D007371:Interferon-gamma / Q000008:administration & dosage / Q000097:blood / Q000235:genetics / Q000633:toxicity*; D008251:Macaca; D008297:Male; D016482:Urinalysis
D000914:Antibodies, Viral; D007371:Interferon-gamma