Safety profile after prolonged C3 inhibition

Edimara S. Reis, Nadja Berger, Xin Wang, Sophia Koutsogiannaki, Robert K. Doot, Justin T. Gumas, Periklis G. Foukas, Ranillo R.G. Resuello, Joel V. Tuplano, David Kukis, Alice F Tarantal, Anthony J. Young, Tetsuhiro Kajikawa, Athena Soulika, Dimitrios C. Mastellos, Despina Yancopoulou, Ali Reza Biglarnia, Markus Huber-Lang, George Hajishengallis, Bo Nilsson & 1 others John D. Lambris

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)96-106
Number of pages11
JournalClinical Immunology
Volume197
DOIs
StatePublished - Dec 1 2018

Fingerprint

Safety
Complement C3
Infection
Primates
Macaca fascicularis
Foreign Bodies
Macaca mulatta
Phagocytosis
Bacterial Infections
Wound Healing
Immune System
Therapeutics
Control Groups
Skin
Wounds and Injuries
compstatin

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Reis, E. S., Berger, N., Wang, X., Koutsogiannaki, S., Doot, R. K., Gumas, J. T., ... Lambris, J. D. (2018). Safety profile after prolonged C3 inhibition. Clinical Immunology, 197, 96-106. https://doi.org/10.1016/j.clim.2018.09.004

Safety profile after prolonged C3 inhibition. / Reis, Edimara S.; Berger, Nadja; Wang, Xin; Koutsogiannaki, Sophia; Doot, Robert K.; Gumas, Justin T.; Foukas, Periklis G.; Resuello, Ranillo R.G.; Tuplano, Joel V.; Kukis, David; Tarantal, Alice F; Young, Anthony J.; Kajikawa, Tetsuhiro; Soulika, Athena; Mastellos, Dimitrios C.; Yancopoulou, Despina; Biglarnia, Ali Reza; Huber-Lang, Markus; Hajishengallis, George; Nilsson, Bo; Lambris, John D.

In: Clinical Immunology, Vol. 197, 01.12.2018, p. 96-106.

Research output: Contribution to journalArticle

Reis, ES, Berger, N, Wang, X, Koutsogiannaki, S, Doot, RK, Gumas, JT, Foukas, PG, Resuello, RRG, Tuplano, JV, Kukis, D, Tarantal, AF, Young, AJ, Kajikawa, T, Soulika, A, Mastellos, DC, Yancopoulou, D, Biglarnia, AR, Huber-Lang, M, Hajishengallis, G, Nilsson, B & Lambris, JD 2018, 'Safety profile after prolonged C3 inhibition', Clinical Immunology, vol. 197, pp. 96-106. https://doi.org/10.1016/j.clim.2018.09.004
Reis ES, Berger N, Wang X, Koutsogiannaki S, Doot RK, Gumas JT et al. Safety profile after prolonged C3 inhibition. Clinical Immunology. 2018 Dec 1;197:96-106. https://doi.org/10.1016/j.clim.2018.09.004
Reis, Edimara S. ; Berger, Nadja ; Wang, Xin ; Koutsogiannaki, Sophia ; Doot, Robert K. ; Gumas, Justin T. ; Foukas, Periklis G. ; Resuello, Ranillo R.G. ; Tuplano, Joel V. ; Kukis, David ; Tarantal, Alice F ; Young, Anthony J. ; Kajikawa, Tetsuhiro ; Soulika, Athena ; Mastellos, Dimitrios C. ; Yancopoulou, Despina ; Biglarnia, Ali Reza ; Huber-Lang, Markus ; Hajishengallis, George ; Nilsson, Bo ; Lambris, John D. / Safety profile after prolonged C3 inhibition. In: Clinical Immunology. 2018 ; Vol. 197. pp. 96-106.
@article{3dbbc2ff3b484312be6ead8fbaa3a478,
title = "Safety profile after prolonged C3 inhibition",
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",
author = "Reis, {Edimara S.} and Nadja Berger and Xin Wang and Sophia Koutsogiannaki and Doot, {Robert K.} and Gumas, {Justin T.} and Foukas, {Periklis G.} and Resuello, {Ranillo R.G.} and Tuplano, {Joel V.} and David Kukis and Tarantal, {Alice F} and Young, {Anthony J.} and Tetsuhiro Kajikawa and Athena Soulika and Mastellos, {Dimitrios C.} and Despina Yancopoulou and Biglarnia, {Ali Reza} and Markus Huber-Lang and George Hajishengallis and Bo Nilsson and Lambris, {John D.}",
year = "2018",
month = "12",
day = "1",
doi = "10.1016/j.clim.2018.09.004",
language = "English (US)",
volume = "197",
pages = "96--106",
journal = "Clinical Immunology",
issn = "1521-6616",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - Safety profile after prolonged C3 inhibition

AU - Reis, Edimara S.

AU - Berger, Nadja

AU - Wang, Xin

AU - Koutsogiannaki, Sophia

AU - Doot, Robert K.

AU - Gumas, Justin T.

AU - Foukas, Periklis G.

AU - Resuello, Ranillo R.G.

AU - Tuplano, Joel V.

AU - Kukis, David

AU - Tarantal, Alice F

AU - Young, Anthony J.

AU - Kajikawa, Tetsuhiro

AU - Soulika, Athena

AU - Mastellos, Dimitrios C.

AU - Yancopoulou, Despina

AU - Biglarnia, Ali Reza

AU - Huber-Lang, Markus

AU - Hajishengallis, George

AU - Nilsson, Bo

AU - Lambris, John D.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

KW - AMY-101

KW - C3

KW - Complement

KW - Compstatin

KW - Cp40

KW - Infection

KW - Inflammation

KW - Non-human primate

UR - http://www.scopus.com/inward/record.url?scp=85053494598&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85053494598&partnerID=8YFLogxK

U2 - 10.1016/j.clim.2018.09.004

DO - 10.1016/j.clim.2018.09.004

M3 - Article

VL - 197

SP - 96

EP - 106

JO - Clinical Immunology

JF - Clinical Immunology

SN - 1521-6616

ER -