The Imidazoquinoline Toll-Like Receptor-7/8 Agonist Hybrid-2 Potently Induces Cytokine Production by Human Newborn and Adult Leukocytes.

Abstract

BACKGROUND:

Newborns and young infants are at higher risk for infections than adults, and manifest suboptimal vaccine responses, motivating a search for novel immunomodulators and/or vaccine adjuvants effective in early life. In contrast to most TLR agonists (TLRA), TLR8 agonists such as imidazoquinolines (IMQs) induce adult-level Th1-polarizing cytokine production from human neonatal cord blood monocytes and are candidate early life adjuvants. We assessed whether TLR8-activating IMQ congeners may differ in potency and efficacy in inducing neonatal cytokine production in vitro, comparing the novel TLR7/8-activating IMQ analogues Hybrid-2, Meta-amine, and Para-amine to the benchmark IMQ resiquimod (R848).

METHODS:

TLRA-induced NF-κB activation was measured in TLR-transfected HEK cells. Cytokine production in human newborn cord and adult peripheral blood and in monocyte-derived dendritic cell cultures were measured by ELISA and multiplex assays. X-ray crystallography characterized the interaction of human TLR8 with Hybrid-2.

RESULTS:

Hybrid-2 selectively activated both TLR7 and 8 and was more potent than R848 in inducing adult-like levels of TNF-α, and IL-1β. Consistent with its relatively high in vitro activity, crystallographic studies suggest that absence in Hybrid-2 of an ether oxygen of the C2-ethoxymethyl substituent, which can engage in unfavorable electrostatic and/or dipolar interactions with the carbonyl oxygen of Gly572 in human TLR8, may confer greater efficacy and potency compared to R848.

CONCLUSIONS:

Hybrid-2 is a selective and potent TLR7/8 agonist that is a candidate adjuvant for early life immunization.

• Authors: Lakshmi Ganapathi, Simon Van Haren, David J Dowling, Ilana Bergelson, Nikunj M Shukla, Subbalakshmi S Malladi, Rajalakshmi Balakrishna, Hiromi Tanji, Umeharu Ohto, Toshiyuki Shimizu, Sunil A David, Ofer Levy
• Journal: PloS one (PLoS One) Vol. 10 Issue 8 Pg. e0134640 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26274907 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Imidazoles
• Immunosuppressive Agents
• Quinolines
• Recombinant Fusion Proteins
• Toll-Like Receptor 7
• Toll-Like Receptor 8
• resiquimod

Topics

• Adult
• Cytokines (metabolism)
• Dendritic Cells (drug effects, metabolism)
• Female
• Fetal Blood (cytology, drug effects, metabolism)
• HEK293 Cells
• Humans
• Imidazoles (pharmacology)
• Immunosuppressive Agents (pharmacology)
• Infant, Newborn
• Leukocytes (drug effects, metabolism)
• Pregnancy
• Quinolines (pharmacology)
• Recombinant Fusion Proteins (pharmacology)
• Toll-Like Receptor 7 (agonists)
• Toll-Like Receptor 8 (agonists)
• Up-Regulation (drug effects)