title: New TLR7 agonists with improved humoral and cellular immune responses.
abstract: Toll-like receptor 7 (TLR7) agonists are of interest as vaccine adjuvants and cancer therapeutics. Therefore, development of new TLR7 agonists that can efficiently promote host immune responses without evoking side effects is of great importance. Here, we describe two new compounds, J4 and F4, which elicit intracellular signaling exclusively via TLR7. Interestingly, both J4 and F4 induced less cytokine secretion (IL-1β, IL-6, IL-10, IL-12p40, TNFα, and IL-12p70) from myeloid dendritic cells (mDCs) and monocytes than CL075 and R848; however, they all generated similar levels of phenotype maturation of antigen presenting cells (APCs), including plasmacytoid DCs. We further found that J4- and F4-induced APC activation was largely dependent on the activation of NF-κB and p38. Lastly, J4 and F4 could efficiently promote B cell proliferation and plasmablast differentiation as well as antigen-specific CD8(+) T cell responses in human in vitro. Therefore, these new TLR7 agonists could be employed to facilitate the development of new therapeutics and vaccine adjuvants against cancers and microbial infections.
authors.affiliation: Baylor Institute for Immunology Research, 3434 Live Oak St., Dallas, TX 75204, USA; Baylor University, Institute for Biomedical Studies, One Bear Place #97224, Waco, TX 76798, USA.
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Upchurch
authors.affiliation: Baylor University, Department of Chemistry and Biochemistry, One Bear Place #97348, Waco, TX 76798, USA.
authors.forename: José R
authors.initials: JR
authors.lastname: Boquín
authors.affiliation: Baylor Institute for Immunology Research, 3434 Live Oak St., Dallas, TX 75204, USA; Baylor University, Institute for Biomedical Studies, One Bear Place #97224, Waco, TX 76798, USA.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Yin
authors.affiliation: Baylor Institute for Immunology Research, 3434 Live Oak St., Dallas, TX 75204, USA.
authors.forename: Yaming
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Baylor Institute for Immunology Research, 3434 Live Oak St., Dallas, TX 75204, USA; Baylor University, Institute for Biomedical Studies, One Bear Place #97224, Waco, TX 76798, USA.
authors.forename: HyeMee
authors.initials: H
authors.lastname: Joo
authors.affiliation: Baylor Institute for Immunology Research, 3434 Live Oak St., Dallas, TX 75204, USA; Baylor University, Institute for Biomedical Studies, One Bear Place #97224, Waco, TX 76798, USA; Baylor University, Department of Chemistry and Biochemistry, One Bear Place #97348, Waco, TX 76798, USA.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Kane
authors.affiliation: Baylor Institute for Immunology Research, 3434 Live Oak St., Dallas, TX 75204, USA; Baylor University, Institute for Biomedical Studies, One Bear Place #97224, Waco, TX 76798, USA. Electronic address: sangkono@baylorhealth.edu.
authors.forename: SangKon
authors.initials: S
authors.lastname: Oh
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000494:pharmacology*; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects* / Q000276:immunology; D056724:Immunity, Humoral / Q000187:drug effects* / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D000241:Adenosine
keywords: Adjuvant; Dendritic Cell; TLR7; Vaccine