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Cutaneous Pharmacodynamics of a Toll-Like Receptor 7 Agonist, 852A, in Humans

From the Department of Medical and Scientific Affairs (former employees Drs Astry and Meng), Department of Pharmacology (Dr Birmachu), and Department of Pharmacokinetics/Drug Metabolism (Dr Harrison), 3M Pharmaceuticals, St Paul, Minnesota.

852A is a specific toll-like receptor 7 (TLR7) agonist. Thirty-two healthy adults (8 subjects per group) received two 1-g topical applications over 400 cm², separated by 5 days, of 852A 0.01% followed by vehicle, vehicle followed by 852A 0.1%, 852A 0.3% followed by vehicle, or vehicle followed by 852A 1.0%. Systemic absorption was minimal as 852A was not quantifiable in any serum sample up to 24 hours postadministration and was only quantifiable at 24 hours in the urine of 4 of 8 subjects after application of 852A 1.0%. No systemic adverse events were associated with drug treatment. Gene expression analysis from application site biopsies showed a 2-fold increase in expression for 40 genes in at least 2 subjects. CXCL9/MIG (8/32 subjects), CCL2/MCP1 (7/32), and OAS3 (5/32) were most frequently increased, followed by other type I interferon-inducible genes. Cluster analysis of the genes with a 2-fold increase did not reveal a definitive pattern with respect to 852A concentration or time of biopsy. Overall, single topical application of 852A up to 1.0% was well tolerated. Data gathered from these subjects are suggestive that 852A can produce increases in local gene expression consistent with TLR7 stimulation.

Key Words: 852A • toll-like receptor 7 • cutaneous pharmacodynamics • innate immunity • gene expression

Address for reprints: Lester I. Harrison, 3M Pharmaceuticals, Department of Pharmacokinetics/Drug Metabolism, 3M Center Bldg 260-3A-05, St. Paul, MN 55144; e-mail: liharrison{at}mmm.com.

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