A safety evaluation of DAS181, a sialidase fusion protein, in rodents.

Abstract

DAS181 is a novel inhaled drug candidate blocking influenza virus (IFV) and parainfluenza virus (PIV) infections through removal of sialic acid receptors from epithelial surface of the respiratory tract. To support clinical development, a 28-day Good Laboratory Practices inhalation toxicology study was conducted in Sprague-Dawley rats. In this study, achieved average daily doses based on exposure concentrations were 0.47, 0.90, 1.55, and 3.00 mg/kg/day of DAS181 in a dry powder formulation. DAS181 was well tolerated at all dose levels, and there were no significant toxicological findings. DAS181 administration did not affect animal body weight, food consumption, clinical signs, ophthalmology, respiratory parameters, or organ weight. Gross pathology evaluations were unremarkable. Histological examination of the lungs was devoid of pulmonary tissue damage, and findings were limited to mild and transient changes indicative of exposure and clearance of a foreign protein. DAS181 did not show any cytotoxic effects on human and animal primary cells, including hepatocytes, skeletal muscle cells, osteoblasts, or respiratory epithelial cells. DAS181 did not cause direct or indirect hemolysis. A laboratory abnormality observed in the 28-day toxicology study was mild and transient anemia in male rats at the 3.00 mg/kg dose, which is an expected outcome of enhanced clearance of desialylated red blood cells resulting from systemic exposure with DAS181. Another laboratory observation was a transient dose-dependent elevation in alkaline phosphatase (ALP), which can be attributed to reduced ALP clearance resulting from increased protein desialylation due to DAS181 systemic exposure. These laboratory parameters returned to normal at the end of the recovery period.

• Authors: Jeffrey L Larson, Seong-Kwi Kang, Bo In Choi, Maria Hedlund, Laura M Aschenbrenner, Beth Cecil, Gloriamay Machado, Matthew Nieder, Fang Fang
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 122 Issue 2 Pg. 567-78 (Aug 2011) ISSN: 1096-0929 [Electronic] United States
• PMID: 21572096 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Recombinant Fusion Proteins
• oplunofusp
• Alkaline Phosphatase
• Neuraminidase

Topics

• Alkaline Phosphatase (analysis)
• Animals
• Cell Line
• Drug Evaluation, Preclinical
• Female
• Hepatocytes (drug effects)
• Humans
• Inhalation Exposure
• Lung (drug effects)
• Male
• Mice
• Mice, Inbred BALB C
• Neuraminidase (pharmacology, toxicity)
• Orthomyxoviridae (drug effects)
• Rats
• Rats, Sprague-Dawley
• Recombinant Fusion Proteins (pharmacology, toxicity)
• Toxicity Tests