Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease

Ahmet Ozen; Nurhan Kasap; Ivan Vujkovic-Cvijin; Richard Apps; Foo Cheung; Elif Karakoc-Aydiner; Bilge Akkelle; Sinan Sari; Engin Tutar; Figen Ozcay; Dilara Kocacik Uygun; Ali Islek; Gamze Akgun; Merve Selcuk; Oya Balci Sezer; Yu Zhang; Gunsel Kutluk; Erdem Topal; Ersin Sayar; Cigdem Celikel; Roderick H J Houwen; Aysen Bingol; Ismail Ogulur; Sevgi Bilgic Eltan; Andrew L Snow; Camille Lake; Giovanna Fantoni; Camille Alba; Brian Sellers; Samuel D Chauvin; Clifton L Dalgard; Olivier Harari; Yan G Ni; Ming-Dauh Wang; Kishor Devalaraja-Narashimha; Poorani Subramanian; Rabia Ergelen; Reha Artan; Sukru Nail Guner; Buket Dalgic; John Tsang; Yasmine Belkaid; Deniz Ertem; Safa Baris; Michael J Lenardo

doi:10.1038/s41590-020-00830-z

Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease

Ahmet Ozen, Nurhan Kasap, Ivan Vujkovic-Cvijin, Richard Apps, Foo Cheung, Elif Karakoc-Aydiner, Bilge Akkelle, Sinan Sari, Engin Tutar, Figen Ozcay, Dilara Kocacik Uygun, Ali Islek, Gamze Akgun, Merve Selcuk, Oya Balci Sezer, Yu Zhang, Gunsel Kutluk, Erdem Topal, Ersin Sayar, Cigdem CelikelRoderick H J Houwen, Aysen Bingol, Ismail Ogulur, Sevgi Bilgic Eltan, Andrew L Snow, Camille Lake, Giovanna Fantoni, Camille Alba, Brian Sellers, Samuel D Chauvin, Clifton L Dalgard, Olivier Harari, Yan G Ni, Ming-Dauh Wang, Kishor Devalaraja-Narashimha, Poorani Subramanian, Rabia Ergelen, Reha Artan, Sukru Nail Guner, Buket Dalgic, John Tsang, Yasmine Belkaid, Deniz Ertem, Safa Baris, Michael J Lenardo

Child Health

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.

Original language	English
Pages (from-to)	128-139
Number of pages	12
Journal	Nature immunology
Volume	22
Issue number	2
Early online date	4 Jan 2021
DOIs	https://doi.org/10.1038/s41590-020-00830-z
Publication status	Published - Feb 2021

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10.1038/s41590-020-00830-z

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Ozen, A., Kasap, N., Vujkovic-Cvijin, I., Apps, R., Cheung, F., Karakoc-Aydiner, E., Akkelle, B., Sari, S., Tutar, E., Ozcay, F., Uygun, D. K., Islek, A., Akgun, G., Selcuk, M., Sezer, O. B., Zhang, Y., Kutluk, G., Topal, E., Sayar, E., ... Lenardo, M. J. (2021). Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease. Nature immunology, 22(2), 128-139. https://doi.org/10.1038/s41590-020-00830-z

@article{a492fae6ff344bdfaf711fdf4a13eb4c,

title = "Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease",

abstract = "Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.",

author = "Ahmet Ozen and Nurhan Kasap and Ivan Vujkovic-Cvijin and Richard Apps and Foo Cheung and Elif Karakoc-Aydiner and Bilge Akkelle and Sinan Sari and Engin Tutar and Figen Ozcay and Uygun, {Dilara Kocacik} and Ali Islek and Gamze Akgun and Merve Selcuk and Sezer, {Oya Balci} and Yu Zhang and Gunsel Kutluk and Erdem Topal and Ersin Sayar and Cigdem Celikel and Houwen, {Roderick H J} and Aysen Bingol and Ismail Ogulur and Eltan, {Sevgi Bilgic} and Snow, {Andrew L} and Camille Lake and Giovanna Fantoni and Camille Alba and Brian Sellers and Chauvin, {Samuel D} and Dalgard, {Clifton L} and Olivier Harari and Ni, {Yan G} and Ming-Dauh Wang and Kishor Devalaraja-Narashimha and Poorani Subramanian and Rabia Ergelen and Reha Artan and Guner, {Sukru Nail} and Buket Dalgic and John Tsang and Yasmine Belkaid and Deniz Ertem and Safa Baris and Lenardo, {Michael J}",

note = "Funding Information: This work was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, BCBB Support Services Contract HHSN316201300006W/HHSN27200002, and The Marmara University, Scientific Research Projects Committee (BAPKO, grant no. SAG-C-TUP-230119-0018). We thank the Turkish National Society of Allergy and Clinical Immunology (TNSACI) for supporting travel expenses for the screening studies. We thank C. Kemper of the National Heart, Lung and Blood Institute for thoughtful editing of the final manuscript. We thank M. Qui{\~n}ones, the Center for Human Immunology and the NIAID Microbiome Program, NIAID, NIH, for research support. We also thank A. Kiykim for patient care, A. Dalga and I. Tatli for technical assistance and H. Su and X. He for advice and assistance; D. Comrie, S. Kubo and J. Ravell for critical reading of the manuscript; and R. Kissinger for artwork. We thank important colleagues at Regeneron: A. N. Thomas for sample processing; C. Huang for biomarker analysis; H. Qiu, and E. Sook Yen for eculizumab analysis; and C. H. Lai, L. DeStefano and K. Donohue for total C5 analysis. Molecular graphics and analyses were performed with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization and Informatics at the University of California, San Francisco, with support from NIH R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, NIAID. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = feb,

doi = "10.1038/s41590-020-00830-z",

language = "English",

volume = "22",

pages = "128--139",

journal = "Nature immunology",

issn = "1529-2908",

publisher = "Nature Publishing Group",

number = "2",

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Ozen, A, Kasap, N, Vujkovic-Cvijin, I, Apps, R, Cheung, F, Karakoc-Aydiner, E, Akkelle, B, Sari, S, Tutar, E, Ozcay, F, Uygun, DK, Islek, A, Akgun, G, Selcuk, M, Sezer, OB, Zhang, Y, Kutluk, G, Topal, E, Sayar, E, Celikel, C, Houwen, RHJ, Bingol, A, Ogulur, I, Eltan, SB, Snow, AL, Lake, C, Fantoni, G, Alba, C, Sellers, B, Chauvin, SD, Dalgard, CL, Harari, O, Ni, YG, Wang, M-D, Devalaraja-Narashimha, K, Subramanian, P, Ergelen, R, Artan, R, Guner, SN, Dalgic, B, Tsang, J, Belkaid, Y, Ertem, D, Baris, S & Lenardo, MJ 2021, 'Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease', Nature immunology, vol. 22, no. 2, pp. 128-139. https://doi.org/10.1038/s41590-020-00830-z

TY - JOUR

T1 - Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease

AU - Ozen, Ahmet

AU - Kasap, Nurhan

AU - Vujkovic-Cvijin, Ivan

AU - Apps, Richard

AU - Cheung, Foo

AU - Karakoc-Aydiner, Elif

AU - Akkelle, Bilge

AU - Sari, Sinan

AU - Tutar, Engin

AU - Ozcay, Figen

AU - Uygun, Dilara Kocacik

AU - Islek, Ali

AU - Akgun, Gamze

AU - Selcuk, Merve

AU - Sezer, Oya Balci

AU - Zhang, Yu

AU - Kutluk, Gunsel

AU - Topal, Erdem

AU - Sayar, Ersin

AU - Celikel, Cigdem

AU - Houwen, Roderick H J

AU - Bingol, Aysen

AU - Ogulur, Ismail

AU - Eltan, Sevgi Bilgic

AU - Snow, Andrew L

AU - Lake, Camille

AU - Fantoni, Giovanna

AU - Alba, Camille

AU - Sellers, Brian

AU - Chauvin, Samuel D

AU - Dalgard, Clifton L

AU - Harari, Olivier

AU - Ni, Yan G

AU - Wang, Ming-Dauh

AU - Devalaraja-Narashimha, Kishor

AU - Subramanian, Poorani

AU - Ergelen, Rabia

AU - Artan, Reha

AU - Guner, Sukru Nail

AU - Dalgic, Buket

AU - Tsang, John

AU - Belkaid, Yasmine

AU - Ertem, Deniz

AU - Baris, Safa

AU - Lenardo, Michael J

N1 - Funding Information: This work was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, BCBB Support Services Contract HHSN316201300006W/HHSN27200002, and The Marmara University, Scientific Research Projects Committee (BAPKO, grant no. SAG-C-TUP-230119-0018). We thank the Turkish National Society of Allergy and Clinical Immunology (TNSACI) for supporting travel expenses for the screening studies. We thank C. Kemper of the National Heart, Lung and Blood Institute for thoughtful editing of the final manuscript. We thank M. Quiñones, the Center for Human Immunology and the NIAID Microbiome Program, NIAID, NIH, for research support. We also thank A. Kiykim for patient care, A. Dalga and I. Tatli for technical assistance and H. Su and X. He for advice and assistance; D. Comrie, S. Kubo and J. Ravell for critical reading of the manuscript; and R. Kissinger for artwork. We thank important colleagues at Regeneron: A. N. Thomas for sample processing; C. Huang for biomarker analysis; H. Qiu, and E. Sook Yen for eculizumab analysis; and C. H. Lai, L. DeStefano and K. Donohue for total C5 analysis. Molecular graphics and analyses were performed with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization and Informatics at the University of California, San Francisco, with support from NIH R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, NIAID. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/2

Y1 - 2021/2

N2 - Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.

AB - Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.

UR - http://www.scopus.com/inward/record.url?scp=85098779482&partnerID=8YFLogxK

U2 - 10.1038/s41590-020-00830-z

DO - 10.1038/s41590-020-00830-z

M3 - Article

C2 - 33398182

SN - 1529-2908

VL - 22

SP - 128

EP - 139

JO - Nature immunology

JF - Nature immunology

IS - 2

ER -

Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease

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