Silencing hepatic complement factor B inhibits alternative pathway activation and attenuates arthritis in CAIA model
10 affiliations
- 1AstraZeneca, Immunology Biosciences, Respiratory and Immunology, BioPharmaceuticals R&D, Gaithersburg, MD 20878, USA
- 2Alexion, AstraZeneca Rare Disease, New Haven, CT 06510, USA
- 3Dicerna Pharmaceuticals, Inc, a Novo Nordisk Company, Lexington, MA 02421, USA
- 4AstraZeneca, Translational Science and Experimental Medicine, Respiratory and Immunology, BioPharmaceuticals R&D, Pepparedsleden 1, 431 83 Mölndal, Sweden
- 5AstraZeneca, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, Gaithersburg, MD 20878, USA
- 6AstraZeneca, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, Pepparedsleden 1, 431 83 Mölndal, Sweden
- 7AstraZeneca, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, Cambridge CB2 0AA, UK
- 8AstraZeneca, Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, Pepparedsleden 1, 431 83 Mölndal, Sweden
- 9Alexion, AstraZeneca Rare Disease, Boston, MA 02210, USA
- 10AstraZeneca, Clinical Development, Respiratory and Immunology, BioPharmaceuticals R&D, Cambridge CB2 0AA, UK
Abstract
The complement system comprises tightly regulated enzymatic cascades that are essential for innate immune defense and tissue homeostasis. Although protective under physiological conditions, complement dysregulation can drive inflammation and tissue injury and contributes to the pathogenesis of autoimmune and inflammatory diseases, prompting the development of complement-targeted therapies. Here, we describe the development and nonclinical evaluation of AZD6912, a GalNAc-conjugated small interfering RNA (siRNA) designed to silence hepatic complement factor B (CFB) as a potential treatment for rheumatoid arthritis. AZD6912 produced potent on-target knockdown of CFB in a hepatocyte cell line and a primary human hepatocyte spheroid model, with no evidence of off-target effects. In mice, a surrogate siRNA targeting hepatic Cfb achieved >90% reduction in liver Cfb mRNA and >95% reduction in circulating CFB protein. This target-specific silencing reduced local complement production, attenuated joint inflammation, and provided therapeutic benefit in the collagen antibody-induced arthritis (CAIA) model. In non-human primates, AZD6912 showed high hepatic exposure, >80% suppression of hepatic CFB mRNA, sustained reductions in serum CFB, and >95% inhibition of complement activity. Safety assessments were unremarkable. Collectively, these findings demonstrate durable siRNA-mediated silencing of CFB with downstream pharmacologic and therapeutic effects, support the clinical development of AZD6912, and highlight the potential of GalNAc-siRNA therapeutics in immune-mediated diseases.
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BibTeX
@article{kuriakose2026silencing,
title = {{Silencing hepatic complement factor B inhibits alternative pathway activation and attenuates arthritis in CAIA model}},
author = {Teneema Kuriakose and Kristi Moore and Natalie Pursell and Utsav Saxena and Feiran Zhang and Henryk Dudek and Jihye Park and Nicole Spiegelman and Wei Zhou and Cecilia S. Leung and Cheng Lai and Girish Chopda and Lucie Bertrand and Mia Collins and T Scott Manetz and Sebastian Prill and Jennifer Y. Tan and Kim Clarke and Nicola Guzzi and Eden Hicks and Gabriel Wong and Patrick Riley and Kyriakos V. Konstantinidis and David Close and Susan Faas and Melissa Lasaro and Gary P. Sims},
journal = {Molecular Therapy. Nucleic Acids},
year = {2026},
month = oct,
doi = {10.1016/j.omtn.2026.103137},
url = {https://doi.org/10.1016/j.omtn.2026.103137},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Silencing hepatic complement factor B inhibits alternative pathway activation and attenuates arthritis in CAIA model
AU - Teneema Kuriakose
AU - Kristi Moore
AU - Natalie Pursell
AU - Utsav Saxena
AU - Feiran Zhang
AU - Henryk Dudek
AU - Jihye Park
AU - Nicole Spiegelman
AU - Wei Zhou
AU - Cecilia S. Leung
AU - Cheng Lai
AU - Girish Chopda
AU - Lucie Bertrand
AU - Mia Collins
AU - T Scott Manetz
AU - Sebastian Prill
AU - Jennifer Y. Tan
AU - Kim Clarke
AU - Nicola Guzzi
AU - Eden Hicks
AU - Gabriel Wong
AU - Patrick Riley
AU - Kyriakos V. Konstantinidis
AU - David Close
AU - Susan Faas
AU - Melissa Lasaro
AU - Gary P. Sims
PY - 2026
DA - 2026/10/12
JO - Molecular Therapy. Nucleic Acids
DO - 10.1016/j.omtn.2026.103137
UR - https://doi.org/10.1016/j.omtn.2026.103137
AB - The complement system comprises tightly regulated enzymatic cascades that are essential for innate immune defense and tissue homeostasis. Although protective under physiological conditions, complement dysregulation can drive inflammation and tissue injury and contributes to the pathogenesis of autoimmune and inflammatory diseases, prompting the development of complement-targeted therapies. Here, we describe the development and nonclinical evaluation of AZD6912, a GalNAc-conjugated small interfering RNA (siRNA) designed to silence hepatic complement factor B (CFB) as a potential treatment for rheumatoid arthritis. AZD6912 produced potent on-target knockdown of CFB in a hepatocyte cell line and a primary human hepatocyte spheroid model, with no evidence of off-target effects. In mice, a surrogate siRNA targeting hepatic Cfb achieved >90% reduction in liver Cfb mRNA and >95% reduction in circulating CFB protein. This target-specific silencing reduced local complement production, attenuated joint inflammation, and provided therapeutic benefit in the collagen antibody-induced arthritis (CAIA) model. In non-human primates, AZD6912 showed high hepatic exposure, >80% suppression of hepatic CFB mRNA, sustained reductions in serum CFB, and >95% inhibition of complement activity. Safety assessments were unremarkable. Collectively, these findings demonstrate durable siRNA-mediated silencing of CFB with downstream pharmacologic and therapeutic effects, support the clinical development of AZD6912, and highlight the potential of GalNAc-siRNA therapeutics in immune-mediated diseases.
SN - 2162-2531
ER -