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Mark Milton, Laura Dill Morton, Birgit Jaitner, David A Shaw, Timothy MacLachlan; Anti-C5 mAb: In Vivo Effects Following Intravitreal Administration to Cynomolgus Monkeys. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1176.
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© ARVO (1962-2015); The Authors (2016-present)
To characterize the in vivo effects of LFG316, a recombinant anti-C5 IgG1 monoclonal antibody after intravitreal (IVT) administration to cynomolgus monkeys
Male and female cynomolgus monkeys were administered repeated (0, 3, or 5 mg/eye every two weeks) 50 µL intravitreal injections of LFG316 for either 3 or 6 months
After intravitreal administration, LFG316 distributed slowly out of the eye and into the systemic circulation with the maximum serum concentrations of total LFG316 occurring at ~ 5 days post dose. The shape of the total LFG316 serum concentration versus time curve was typical for the extravascular administration of a monoclonal antibody. At all dose levels, LFG316 could be detected throughout the dose interval and the duration of the study. Appearance of LFG316 in serum is accompanied by a similar molar increase in total C5 serum concentration; indicating that LFG316 in serum is mostly complexed to C5. Consequently, there was no evidence of pharmacodynamic activity (as measured by the hemolysis of rabbit red blood cells by serum samples) from systemic exposure to LFG316, since apparent free C5 concentration in serum (approximated by total C5 minus total LFG316) is not affected. Anti-LFG316 antibodies were detected in 1/24 and 3/20 monkeys in the 3-month and 6-month studies, respectively. There were no treatment-related mortalities or findings regarding clinical observations, body weights, estimated food consumption, ophthalmoscopy, intra-ocular pressure, electroretinography, electrocardiography, blood pressure, immunophenotyping, hematology, clinical chemistry, urine analysis, organ weights or histopathology that could be attributed to treatment with LFG316
LFG316 was well tolerated in cynomolgus monkeys after multiple intravitreal injections up to a dose of 5 mg/eye every other week for up to 6 months. LFG316 distributed from the eye into the serum, bound to C5 in the serum but the amount of target (C5) capture was low, leading to no observable impact on the activity of the alternative complement pathway in the serum
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