Activation of Innate Immunity in Healthy Macaca mulatta Macaques by a Single Subcutaneous Dose of GMP CpG 7909: Safety Data and Interferon-Inducible Protein-10 Kinetics for Humans and Macaques
| Autor: | Evelina Angov, Noelle S. Larson, Arthur M. Krieg, Shannon McGrath, Thomas G. Brewer, V. Ann Stewart, D. Gray Heppner, Christopher L. Smith |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Microbiology (medical) Agonist medicine.drug_class Injections Subcutaneous Clinical Biochemistry Immunology Dose-Response Relationship Immunologic Inflammation In Vitro Techniques Biology Adjuvants Immunologic Interferon medicine Animals Humans Immunology and Allergy Receptor Skin Innate immune system Cellular Immunology Antibodies and Mediators of Immunity TLR9 biology.organism_classification Macaca mulatta Immunity Innate Chemokine CXCL10 Rhesus macaque Oligodeoxyribonucleotides CpG site Female Lymph Nodes medicine.symptom medicine.drug |
| Zdroj: | Clinical and Vaccine Immunology. 15:221-226 |
| ISSN: | 1556-679X 1556-6811 |
| DOI: | 10.1128/cvi.00420-07 |
| Popis: | Following a demonstration that mouse-optimized cytosine-guanosine dinucleotide (CpG) oligodeoxynucleotides stimulated innate immune protection against intracellular pathogens, we tested the ability of CpG 7909, a primate-optimized Toll-like receptor 9 (TLR9) agonist, to stimulate rhesus macaques to produce interferon-inducible protein-10 (IP-10), a biomarker of immune activation. This study was performed prior to a similar trial with humans in order to facilitate the development of CpG 7909 as an immunomodulator for biodefense. A single subcutaneous dose of clinical-grade CpG 7909 was given to four groups of healthy adult rhesus macaques (0-mg dose [ n = 5], 0.75-mg dose [ n = 9], 1.5-mg dose [ n = 9], and 3.0-mg dose [ n = 9]). Directed physical examination findings, clinical laboratory values, and serum IP-10 concentrations were collected at scheduled intervals for 28 days. All three dose levels of CpG 7909 were safe and not associated with significant clinical or laboratory abnormality. The time to peak serum IP-10 concentration was 1.0 days at the 0.75-mg dose and 0.5 days at the 1.5- and 3.0-mg doses. A dose-dependent response was observed for the magnitude and duration of IP-10 concentrations, which remained significantly above baseline for 3 days for the 3.0-mg and 1.5-mg dose groups but above baseline for only 2 days for the 0.75-mg dose group. There were no nonresponders to CpG 7909. These rhesus macaque safety and IP-10 response data closely parallel a subsequent phase 1 human study of subcutaneously administered CpG 7909. A single dose of clinical-grade CpG 7909 induced a rapid, sustained IP-10 response, a biomarker for activation of the innate immune system. Given the similar susceptibilities of humans and rhesus macaques to infectious diseases, the rhesus macaque appears to be a suitable model to evaluate the potential of CpG 7909-mediated innate immune activation to protect humans against pathogens. |
| Databáze: | OpenAIRE |
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