Τίτλος:
Safety profile after prolonged C3 inhibition
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
The central component of the complement cascade, C3, is involved in various biological functions, including opsonization of foreign bodies, clearance of waste material, activation of immune cells, and triggering of pathways controlling development. Given its broad role in immune responses, particularly in phagocytosis and the clearance of microbes, a deficiency in complement C3 in humans is often associated with multiple bacterial infections. Interestingly, an increased susceptibility to infections appears to occur mainly in the first two years of life and then wanes throughout adulthood. In view of the well-established connection between C3 deficiency and infections, therapeutic inhibition of complement at the level of C3 is often considered with caution or disregarded. We therefore set out to investigate the immune and biochemical profile of non-human primates under prolonged treatment with the C3 inhibitor compstatin (Cp40 analog). Cynomolgus monkeys were dosed subcutaneously with Cp40, resulting in systemic inhibition of C3, for 1 week, 2 weeks, or 3 months. Plasma concentrations of both C3 and Cp40 were measured periodically and complete saturation of plasma C3 was confirmed. No differences in hematological, biochemical, or immunological parameters were identified in the blood or tissues of animals treated with Cp40 when compared to those injected with vehicle alone. Further, skin wounds showed no signs of infection in those treated with Cp40. In fact, Cp40 treatment was associated with a trend toward accelerated wound healing when compared with the control group. In addition, a biodistribution study in a rhesus monkey indicated that the distribution of Cp40 in the body is associated with the presence of C3, concentrating in organs that accumulate blood and produce C3. Overall, our data suggest that systemic C3 inhibition in healthy adult non-human primates is not associated with a weakened immune system or susceptibility to infections. © 2018 Elsevier Inc.
Συγγραφείς:
Reis, E.S.
Berger, N.
Wang, X.
Koutsogiannaki, S.
Doot, R.K.
Gumas, J.T.
Foukas, P.G.
Resuello, R.R.G.
Tuplano, J.V.
Kukis, D.
Tarantal, A.F.
Young, A.J.
Kajikawa, T.
Soulika, A.M.
Mastellos, D.C.
Yancopoulou, D.
Biglarnia, A.-R.
Huber-Lang, M.
Hajishengallis, G.
Nilsson, B.
Lambris, J.D.
Περιοδικό:
Clinical Immunology Newsletter
Εκδότης:
Academic Press Inc.
Λέξεις-κλειδιά:
complement component C3 inhibitor; cp 40; cp40 i 124; ketorolac; tracer; unclassified drug; wound healing promoting agent; complement component C3; complement inhibitor; compstatin; cyclopeptide, adult; animal cell; animal experiment; animal model; animal tissue; Article; comparative study; controlled study; drug half life; drug safety; drug tissue level; female; immunological parameters; in vivo study; limit of quantitation; long term exposure; Macaca fascicularis; male; maximum concentration; nonhuman; pharmacokinetic parameters; positron emission tomography-computed tomography; priority journal; punch biopsy; quantitative analysis; real time polymerase chain reaction; reversed phase liquid chromatography; skin biopsy; skin injury; wound healing; animal; immunology; injury; metabolism; rhesus monkey; time factor; tissue distribution; wound healing; wound infection, Animals; Complement C3; Complement Inactivating Agents; Macaca fascicularis; Macaca mulatta; Peptides, Cyclic; Time Factors; Tissue Distribution; Wound Healing; Wound Infection; Wounds and Injuries
DOI:
10.1016/j.clim.2018.09.004
