{
    "abstract": "GSK2245035, a small molecule Toll-like Receptor 7 (TLR7) agonist developed for immunomodulatory treatment for allergic airways disease, aimed to reduce Th2 and enhance Th1/Treg responses to aeroallergens via the local induction of type I interferons (IFNs). GSK2245035 demonstrated selectivity for potent release of type I IFNs compared to TNF-\u03b1 and IL-6, with dose dependent increases in the interferon inducible chemokine, IP-10, in the nasal compartment. Implantation and parturition require pro-inflammatory processes including IFNs, Interferon Stimulated Genes, TNF\u03b1 and IP-10 while pregnancy requires immune regulation to maintain maternal fetal immune tolerance, and recombinant type I IFNs induced abortions in monkeys. Due to its mechanism of action, GSK2245035 was studied at pharmacologically and clinically relevant doses in a monkey pregnancy model. Monkeys received 0, 3 or 30 ng/kg/week GSK2245035 intranasally once weekly, from Day 20 postcoitum through Day 63 postpartum. Although systemic IFN-\u03b1 and IP-10 levels were approximately 14.8 or 40 -fold (respectively) above predose levels at 3 or 30 ng/kg/week, respectively, there were no effects on pregnancy and infant outcome. Non-adverse effects included increased incidence of nasal discharge, increased maternal body temperature at 30 ng/kg/week and dose-dependent increases in maternal IP-10 and IFN-\u03b1 and decreased infant anti-KLH IgM and IgG titers following KLH immunization at \u22653 ng/kg/week, relative to controls. Potentially, lower IFN-\u03b1 and IP-10 levels as well as once-weekly intranasal dosing vs daily subcutaneous or intramuscular dosing with recombinant type I IFNs could explain the lack of pregnancy effects; however, there was an undesired impact on offspring immune function.",
    "authors": [
        {
            "affiliation": "Department of Reproductive Toxicology, Nonclinical Safetyy, GlaxoSmithKline, Upper Providence, PA, USA. Electronic address: lorraine.m.posobiec@gsk.com.",
            "firstname": "L M",
            "initials": "LM",
            "lastname": "Posobiec"
        },
        {
            "affiliation": "Department of ImmunoToxicology, Nonclinical Safety, GlaxoSmithKline, Upper Providence, PA, USA.",
            "firstname": "A E",
            "initials": "AE",
            "lastname": "Hillegas"
        },
        {
            "affiliation": "Covance Laboratories, Inc, Madison Wisconsin, USA.",
            "firstname": "A",
            "initials": "A",
            "lastname": "Baker"
        },
        {
            "affiliation": "Covance Laboratories, Inc, Madison Wisconsin, USA.",
            "firstname": "A S",
            "initials": "AS",
            "lastname": "Phadnis-Moghe"
        },
        {
            "affiliation": "Department of ImmunoToxicology, Nonclinical Safety, GlaxoSmithKline, Upper Providence, PA, USA.",
            "firstname": "C C",
            "initials": "CC",
            "lastname": "Maier"
        },
        {
            "affiliation": "Department of Reproductive Toxicology, Nonclinical Safetyy, GlaxoSmithKline, Upper Providence, PA, USA.",
            "firstname": "D J",
            "initials": "DJ",
            "lastname": "Stanislaus"
        },
        {
            "affiliation": "Department of Research Statistics, GlaxoSmithKline, Upper Providence, PA, USA.",
            "firstname": "M",
            "initials": "M",
            "lastname": "Bray"
        },
        {
            "affiliation": "Department of Translation Platform Project Specialists, Nonclinical Safety, GlaxoSmithKline, UK.",
            "firstname": "M A",
            "initials": "MA",
            "lastname": "Price"
        }
    ],
    "conclusions": null,
    "copyrights": "Copyright \u00a9 2020 Elsevier B.V. All rights reserved.",
    "doi": "10.1016/j.jri.2020.103242",
    "journal": "Journal of reproductive immunology",
    "keywords": [
        "TLR7",
        "cytokine",
        "ePPND",
        "infant KLH TDAR",
        "intranasal",
        "monkey"
    ],
    "methods": null,
    "publication_date": "2020-11-20",
    "pubmed_id": "33212303",
    "results": null,
    "title": "GSK2245035, a TLR7 agonist, Does Not Increase Pregnancy Loss in Cynomolgus Monkeys.",
    "xml": "<Element 'PubmedArticle' at 0x788503dade90>"
}