An experimental study of PEGylated interferon lambda-1 chronic toxicity

I n t r o d u c t i o n . Lambda interferons (IFN-λ), known as type III interferons (type III IFN), demonstrate significant prospects in the field of antivirus defense. IFN-λ are similar in their antiviral activity to type I IFN, but have unique mechanisms of induction and functioning because of the specific location of their receptors. Type I receptors are expressed in most nucleated cells, IFN-λ receptors (IFN-λR1 or IL-28Rα) are mainly found in epithelial cells. IFN-λ are considered as the first line of defense against microbial attacks, therefore, the development of IFN-λ-based drugs seems very promising. A prototype of an IFN-λ-based drug for enteral administration, PEGylated (polyethylene glycol) using electron beam synthesis technology, has already been developed.

A i m . To study the common toxic properties of the  intragastrically administered IFN-λ1-based drug in experiments in vivo.

M a t e r i a l s a n d m e t h o d s .  The IFN-λ1-based drug was administered daily intragastrically at doses of 2.6, 13.0 and 26.0 μg/kg (1 therapeutic dose (TD), 5 TD and 10 TD, respectively) to rats and 2.6 and 13.0 μg/kg (1 TD and 5 TD) to rabbits once a day for 180 days. The doses of the drug were calculated for each animal individually, based on body weight. Rabbits were followed-up during the drug administration (180 days), and rats – additionally for 30 days after the end of administration (210 days). In animals, vital signs, behavioral reactions, laboratory parameters of cellular and biochemical composition of blood, electrocardiography data, hematopoiesis parameters, pathomorphological signs were assessed.

R e s u l t s . No deaths were observed during the study. The animals showed a stable state of health, the absence of visible changes in an appetite, appearance, and behavior. During a pathomorphological examination, no abnormalities were found that could indicate a negative effect of the substance. A significant decrease in the mass and mass coefficient of the thymus and spleen was revealed in rats receiving the drug at a dose of 26.0 μg/kg after 180 days of administration compared with the corresponding control.  The thymus and spleen mass and the mass coefficient of the thymus and spleen normalized 30 days after drug withdrawal in all groups, where abnormalities were observed. A microscopic examination of the internal organs of rats receiving the highest dose of  the IFN-λ1-based drug (26.0 μg/kg) for 180 days revealed specific changes in the thymus and spleen, while analysis of the thymus and spleen in rats receiving a lower dose of  the drug (13.0 μg/kg) did not reveal similar pathological changes. This indicates the possibility of dose-dependent toxic effect of the drug. 30 days after the IFN-λ1-based drug withdrawal, the mass and mass coefficient of the thymus and spleen of rats receiving the highest dose of the drug returned to the reference values and did not differ from the corresponding control. Both in rats and rabbits, the indicators of body weight gain, peripheral blood and bone marrow, biochemical parameters of the blood serum in both males and females in the experimental and control groups did not differ significantly throughout the study. The pathomorphological examination found no changes in such crucial organs as the brain, heart, lungs, liver, etc., which indicates the absence of negative effect of the drug on the health and condition of the tissues of rabbits.

C o n c l u s i o n . Based on in vivo experiments to study the common  toxic properties of IFN-λ1-based drug in the intragastric route of administration, it can be argued that the drug belongs to the 4th hazard  class (GOST 12.1.007-76). 

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