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

• Published in: Nature immunology Vol. 22; no. 2; pp. 128 - 139
• Main Authors: Ozen, Ahmet, Kasap, Nurhan, Vujkovic-Cvijin, Ivan, Apps, Richard, Cheung, Foo, Karakoc-Aydiner, Elif, Akkelle, Bilge, Sari, Sinan, Tutar, Engin, Ozcay, Figen, Uygun, Dilara Kocacik, Islek, Ali, Akgun, Gamze, Selcuk, Merve, Sezer, Oya Balci, Zhang, Yu, Kutluk, Gunsel, Topal, Erdem, Sayar, Ersin, Celikel, Cigdem, Houwen, Roderick H. J., Bingol, Aysen, Ogulur, Ismail, Eltan, Sevgi Bilgic, Snow, Andrew L., Lake, Camille, Fantoni, Giovanna, Alba, Camille, Sellers, Brian, Chauvin, Samuel D., Dalgard, Clifton L., Harari, Olivier, Ni, Yan G., Wang, Ming-Dauh, Devalaraja-Narashimha, Kishor, Subramanian, Poorani, Ergelen, Rabia, Artan, Reha, Guner, Sukru Nail, Dalgic, Buket, Tsang, John, Belkaid, Yasmine, Ertem, Deniz, Baris, Safa, Lenardo, Michael J.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2021; Nature Publishing Group
• Subjects: 631/250/2501; 692/699/249/2512; Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Humanized - pharmacokinetics; Antibodies, Monoclonal, Humanized - therapeutic use; Aptamers; Biomarkers - blood; Biomedical and Life Sciences; Biomedicine; CD55 Antigens - deficiency; CD55 Antigens - genetics; Complement activation; Complement Activation - drug effects; Complement C5 - antagonists & inhibitors; Complement C5 - metabolism; Complement component C5; Complement Inactivating Agents - adverse effects; Complement Inactivating Agents - pharmacokinetics; Complement Inactivating Agents - therapeutic use; Energy Metabolism - drug effects; Genetic Predisposition to Disease; Humans; Hypoproteinemia - drug therapy; Hypoproteinemia - genetics; Hypoproteinemia - immunology; Hypoproteinemia - metabolism; Immunity, Innate - drug effects; Immunodeficiency; Immunoglobulins; Immunology; Infectious Diseases; Innate immunity; Intestinal microflora; Intestine; Medical treatment; Microbiomes; Mutation; Pathology; Patients; Pediatrics; Phenotype; Protein-Losing Enteropathies - drug therapy; Protein-Losing Enteropathies - genetics; Protein-Losing Enteropathies - immunology; Protein-Losing Enteropathies - metabolism; Proteins; Serum proteins; Thromboembolism; Thrombosis; Treatment Outcome
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/s41590-020-00830-z

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. CHAPLE disease is a lethal syndrome caused by genetic loss of the complement regulatory protein CD55. Lenardo, Ozen and their colleagues report that blockade of C5 complement activation in a small cohort of pediatric patients with CHAPLE disease reduced gastrointestinal pathology and restored their immunity and growth.