| Recombinant human interferon -β1b(rHuEFN-β1b) is a new biopharmaceutical intended to treat the relapsing-remitting multiple sclerosis (RR-MS). There are no reports on the evaluation of its preclinical long-term toxicity and immnogenicity. The 13-week repeated dose toxicity study in cynomolgus monkeys were conducted to determine the target organ of toxicity and its reversibility, the immunogenicity to a pharmacologically responsive species and the potential adverse immunomodulatory activity of rHuEFN-β1b. The murine local lymph node assay was performed to evaluate the skin sensitization potentiality of rHuIFN-β1b.Three monkeys per sex received daily s.c. injections of either 4.0×10~6, 1.2×107and3.6×107 IU/kg, or 1.25% human serum albumin(HSA) for 13 weeks. Body weights were obtained at baseline on day -7 and on day 0, then at weekly interval for the duration of the study. Clinical observations were performed every day for signs of overt toxicity. body temperature were determined using an electronic thermometer and electrocardigram were recorded on each animal at baseline, and once monthly after dosing. Ophthalmologic examinations were performed on both eyes of each animal at both day 90 and 120. Peripheral blood samples for hematological, serum biochemistry profiles and cytokine ( TGF-β ,TNF- α , IL-4 and IL-10) levels were obtained on day -7 and day 0, then on day 30, 90 and 120. Another blood samples were obtained once weekly from D14 to D120 for the determination of binding (by ELISA) and neutralizing (by cytopathologic inhibition assay) antibody to formulation. At terminal sacrifice, half on dosing termination (day 90) and another half on the end of recovery period (D120), animals were subjected to full necropsy, with gross pathologic evaluation of target tissues. Organs were removed, weighed and individual organ weight: body weight ratios were calculated. Tissue sample were obtained and processed for histopathologic examination.There were no mortalities or overt sign of clinical toxicity present in any of control orrHuIFN-β1b treated animals. Body weights duration the study were not significant different in all groups of animals treated with rHuIFN-β1b, as compared to the controls. There were no weight gains during 5th week to 13th week after dosing in both treatment and control animals, which could be contributed to the stress induced by HSA. No rectal body temperature, electrocardigraphic and ophthalmologic abnormalities were detected in any of the animals on the study after 13 weeks of treatment with 1.25% HSA or rHuIFN-β1b. Hematological profiles were not appreciably altered from baseline, one major finding at week 4 and week 13 time point was an approximated 5-6% and 15% decrease in platelet levels in the high-dose animals. There no definitive changes in clinical chemistry profiles for animals treated with rHuIFN-β1b for 13 weeks, as compared to carrier control group or to baseline values, and urinalysis profiles were not significantly different between the control and rHuIFN-β1b treated monkeys.At necropsy, no treatment-related findings were evident on gross pathological examination of the rHuIFN-β1b treated monkeys. One noted observation was the significant increase in the organ weight: body weight ratios for spleen and thymus of rHuEFN-β1b dosed males, as compared to the control animals. On the histologic evaluation, there no pathologic finding that could be directly related to treatment with rHuIFN-β1b. The only evident abnormality was the widening of space of Disse's in outer area of hepatic lobules. From previous results, it is concluded that the NOAEL for long-term toxicology of rHuIFN-β1b is 3.6×107 IU/kg .Analysis of serum levels of binding and neutralizing anti- rHuEFN-β1b antibodies demonstrates that after 13 weeks of treatment, 87.1 to 87238.1-fold increase in anti-rHuIFN-β1b binding activity had developed in all groups of either control or rHuIFN-Plb treated animals, as compared to the baseline values for these monkeys. And the anti- rHuIFN-β1b titer...
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