2. Academic Validation
  3. Combined antagonism of Oncostatin M (OSM) and Interleukin 6 (IL-6) provides both anti-fibrotic and anti-inflammatory benefit in pulmonary fibrosis

Combined antagonism of Oncostatin M (OSM) and Interleukin 6 (IL-6) provides both anti-fibrotic and anti-inflammatory benefit in pulmonary fibrosis

  • bioRxiv. 2025 Dec 26:2025.12.25.695625. doi: 10.64898/2025.12.25.695625.
Rojo A Ratsimandresy 1,  Emma Doran 1,  Hart S Dengler 1,  Sarah E Headland 1,  Christopher J Wedeles 1,  Riccardo Guidi 1,  Daqi Xu 1,  Jiatong Liu 2,  Yongchang Shi 3,  Jianyong Wang 3,  Salil Uttarwar 4,  Alexander R Abbas 4,  Tianhe Sun 1,  Daryle J DePianto 1,  Katrina B Morshead 1,  Joe Arron 1,  Jason R Rock 1,  Jack Bevers 5,  Rajbharan Yadav 6,  Thirumalai Ramalingam 7,  Xia Gao 7,  Hans D Brightbill 5,  Claire L Emson 8,  Surinder Jeet 8,  Alexander Arlantico 8,  Aaron Wong 8,  Sherman Yu 8,  Tiffany Hao Tran 9,  Laurie Leong 9,  Wennie Chen 9,  Monika Dohse 9,  Cary Austin 9,  Patrick Caplazi 9,  Reynold A Panettieri Jr 10,  Cynthia Koziol-White 10,  William F Jester Jr 10,  Andrey Shaw 11,  Shimrit Avraham 11,  Hari Menon 12,  Spyros Darmanis 12,  Zora Modrusan 12,  Kimberly Kajihara 13,  Masakazu Kanamori 14,  Hideaki Shimada 14,  Nathaniel R West 11,  Gerald Nakamura 5,  Jason A Vander Heiden 1 15,  Mark S Wilson 1
Affiliations

Affiliations

  • 1 Immunology Discovery, Genentech, South San Francisco, California 94080, USA.
  • 2 School of Medicine and Dentistry, University of Rochester Medical Centre, Rochester, New York, 14642, USA.
  • 3 Biochemical and Cellular Pharmacology, Genentech, South San Francisco, California, 94080, USA.
  • 4 OMNI Bioinformatics, Genentech, South San Francisco, California 94080, USA.
  • 5 Antibody Engineering, Genentech, South San Francisco, California 94080, USA.
  • 6 Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech, South San Francisco, California 94080, USA.
  • 7 Biomarker Discovery, Genentech, South San Francisco, California 94080, USA.
  • 8 Translational Immunology, Genentech, South San Francisco, California 94080, USA.
  • 9 Pathology, Genentech, South San Francisco, California 94080, USA.
  • 10 Institute for Translational Medicine and Science, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08901 USA.
  • 11 Discovery Oncology, Genentech, South San Francisco, California 94080, USA.
  • 12 Next Generation Sequencing and Microchemistry, Proteomics and Lipidomics, Genentech, South San Francisco, California 94080, USA.
  • 13 Infectious Disease, Genentech, South San Francisco, California 94080, USA.
  • 14 Chugai Pharmabody Research Pte. Ltd., Singapore.
  • 15 Biological Research AI Development, Genentech, South San Francisco, California 94080, USA.
PMID: 41497665 DOI: 10.64898/2025.12.25.695625
Abstract

Interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated ILD (SSc-ILD), are irreversible fibrosing diseases with a mean survival time of less than 5 years for IPF. Poorly understood etiology and complex pathogenesis of these diseases have hampered the identification and development of effective therapeutics. Existing treatments can slow progressive fibrosis and lung function decline but do not stop it entirely, resulting in a minimal impact on patient survival. Thus, novel therapeutic interventions are needed. Tocilizumab, an anti-IL-6 receptor antibody, was recently approved by FDA for the treatment of SSc-ILD based on evidence demonstrating a reduction in the rate of lung function decline. In this study, we have characterized an IL-6-driven feed-forward myeloid axis contributing to lung inflammation providing a mechanistic hypothesis for tocilizumab. Concomitantly we have identified an oncostatin M (OSM) orchestrated lung injury response contributing to epithelial and endothelial cell disruption, myofibroblast activation and fibrosis. Despite dysregulated expression of IL11 in IPF, SSc-ILD, and murine models of fibrosis, we found no evidence for a pro-fibrotic role for IL-11 in vitro or in vivo. Instead, in pre-clinical models of IPF we demonstrate that antagonism of OSM alone, or to a greater degree in combination with IL-6, reduced lung fibrosis and inflammation. Translating these observations, we validated gp130:OSMR, rather than gp130:LIFR, as the dominant human receptor complex used by OSM, identifying OSMR as a potential therapeutic target to stall fibrosis.

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