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Clin Immunol. 2018 Sep 20;197:96-106. doi: 10.1016/j.clim.2018.09.004. [Epub ahead of print]

Safety profile after prolonged C3 inhibition.

Author information

1
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
2
Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
3
2nd Department of Pathology, National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece.
4
Simian Conservation Breeding and Research Center (SICONBREC), Makati City, Philippines.
5
Center for Molecular and Genomic Imaging, University of California, Davis, CA 95616, USA.
6
Departments of Pediatrics and Cell Biology and Human Anatomy, School of Medicine, and California National Primate Research Center, University of California, Davis, CA 95616, USA.
7
Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
8
Department of Dermatology, University of California, Davis, CA 95616, USA.
9
National Center for Scientific Research 'Demokritos', Athens, Greece.
10
Amyndas Pharmaceuticals, Glyfada, Greece.
11
Department of Transplantation, Skane University Hospital, Lund University, Lund, Sweden.
12
Institute of Clinical and Experimental Trauma-Immunology, University Hospital Ulm, Ulm, Germany.
13
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
14
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: lambris@pennmedicine.upenn.edu.

Abstract

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.

KEYWORDS:

AMY-101; C3; Complement; Compstatin; Cp40; Infection; Inflammation; Non-human primate

PMID:
30217791
DOI:
10.1016/j.clim.2018.09.004

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