Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease

Blood Advances - Tập 5 - Trang 3445-3456 - 2021
Sheila K. Pierson1,2, Sushila Shenoy3, Ana B. Oromendia3, Alexander M. Gorzewski1,2, Ruth-Anne Langan Pai1, Christopher Shield Nabel2, Jason R. Ruth2, Sophia A.T. Parente1,2, Daniel J. Arenas1,2, Mary Guilfoyle4, Manjula Reddy4, Michael Weinblatt5, Nancy Shadick5, Mark Bower6, Alessia Dalla Pria6, Yasufumi Masaki7, Laura Katz3, Jason Mezey8, Philip Beineke3, David Lee3
1Center for Cytokine Storm Treatment & Laboratory, Department of Medicine, University of Pennsylvania, Philadelphia, PA
2Castleman Disease Collaborative Network, Philadelphia, PA
3Medidata Solutions, New York, NY
4Janssen Pharmaceuticals, Raritan, NJ
5Department of Medicine, Brigham and Women's Hospital, Boston, MA
6Department of Medicine, Chelsea & Westminster Hospital, London, United Kingdom
7Department of Hematology and Immunology, Kanazawa Medical University, Ishikawa, Japan
8Department of Genetic Medicine, Weill Cornell Medicine, New York, NY

Tóm tắt

AbstractIdiopathic multicentric Castleman disease (iMCD) is a poorly understood hematologic disorder involving cytokine-induced polyclonal lymphoproliferation, systemic inflammation, and potentially fatal multiorgan failure. Although the etiology of iMCD is unknown, interleukin-6 (IL-6) is an established disease driver in approximately one-third of patients. Anti–IL-6 therapy, siltuximab, is the only US Food and Drug Administration–approved treatment. Few options exist for siltuximab nonresponders, and no validated tests are available to predict likelihood of response. We procured and analyzed the largest-to-date cohort of iMCD samples, which enabled classification of iMCD into disease categories, discovery of siltuximab response biomarkers, and identification of therapeutic targets for siltuximab nonresponders. Proteomic quantification of 1178 analytes was performed on serum of 88 iMCD patients, 60 patients with clinico-pathologically overlapping diseases (human herpesvirus-8–associated MCD, N = 20; Hodgkin lymphoma, N = 20; rheumatoid arthritis, N = 20), and 42 healthy controls. Unsupervised clustering revealed iMCD patients have heterogeneous serum proteomes that did not cluster with clinico-pathologically overlapping diseases. Clustering of iMCD patients identified a novel subgroup with superior response to siltuximab, which was validated using a 7-analyte panel (apolipoprotein E, amphiregulin, serum amyloid P-component, inactivated complement C3b, immunoglobulin E, IL-6, erythropoietin) in an independent cohort. Enrichment analyses and immunohistochemistry identified Janus kinase (JAK)/signal transducer and activator of transcription 3 signaling as a candidate therapeutic target that could potentially be targeted with JAK inhibitors in siltuximab nonresponders. Our discoveries demonstrate the potential for accelerating discoveries for rare diseases through multistakeholder collaboration.

Tài liệu tham khảo

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Blood Advances

Tập 5

3445-3456

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