The designer cytokine IC7Fc attenuates atherosclerosis development by targeting hyperlipidemia in mice PMID: 41134879

ADC Targets in Oncology

2026-04-10

The designer cytokine IC7Fc attenuates atherosclerosis development by targeting hyperlipidemia in mice

Sci Adv. 2025 Oct 24;11(43):eadx3794. doi: 10.1126/sciadv.adx3794.

Wietse In Het Panhuis ¹ ² ³ ⁴ , Ellen Thiemann ¹ ² , Daisy M A H van Dijk ¹ ² , Bibian Been ¹ ² , Kelsey E Jarrett ⁵ , Amber Meurs ⁶ , Sander Kooijman ¹ ² , Milaine V Hovingh ⁷ , Melanie Modder ¹ ² , Bram W van Os ⁸ ⁹ ¹⁰ , Thijs J Sluiter ² ¹¹ , Niek Blomberg ¹² , Amanda C M Pronk ¹ ² , Salwa Afkir ¹ ² , Trea C M Streefland ¹ ² , Reshma A Lalai ¹ ² , Maria O Taveras ¹³ , Sen Zhang ¹ ² , Timothy E Adams ¹⁴ , Lauren V Terry ¹⁵ , Sarah M Turpin-Nolan ¹⁵ , Margreet R de Vries ² ¹¹ ¹⁶ , Martin Giera ¹² , Stefan Rose-John ¹⁷ , Noam Zelcer ⁶ , Jan Freark de Boer ⁷ ¹⁸ , Thomas Q de Aguiar Vallim ⁵ ¹³ , Mark A Febbraio ¹⁵ , Patrick C N Rensen ¹ ² , Milena Schönke ¹ ²

Affiliations

1. Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, Netherlands.
2. Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, Netherlands.
3. Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands.
4. Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, Netherlands.
5. Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
6. Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Gastroenterology Endocrinology Metabolism and Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam, Netherlands.
7. Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
8. Department of Medical Biochemistry, Amsterdam University Medical Centers, Amsterdam, Netherlands.
9. Amsterdam Cardiovascular Sciences, Atherosclerosis & Ischemic Syndromes, Amsterdam, Netherlands.
10. Amsterdam Immunity and Infection, Amsterdam, Netherlands.
11. Department of Surgery, Leiden University Medical Center, Leiden, Netherlands.
12. Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, Netherlands.
13. Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
14. CSIRO Manufacturing, Clayton, Victoria, Australia.
15. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
16. Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
17. Department of Biochemistry, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
18. Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

Abstract

The chimeric cytokine IC7Fc conveys the metabolic signaling properties of the glycoprotein 130 receptor cytokines interleukin-6 and ciliary neurotrophic factor via membrane-bound signaling. IC7Fc was previously shown to slow the progression of type 2 diabetes mellitus, and here, we demonstrate its effect on atherosclerotic development. In APOE*3-Leiden.CETP mice, an atherosclerosis-prone model with a humanized lipoprotein metabolism, IC7Fc markedly lowered plasma triglyceride and total Cholesterol levels. This was mechanistically explained by an inhibition of de novo lipogenesis in the liver, increased synthesis of bile acids from Cholesterol, and down-regulated Apolipoprotein B synthesis, which resulted in decreased Cholesterol secretion in very low-density lipoprotein particles. As a consequence, IC7Fc treatment considerably reduced atherosclerotic lesion formation and vascular inflammation compared with current antihyperlipidemic therapy. In conclusion, IC7Fc is a promising pharmacological treatment for cardiometabolic diseases targeting hyperlipidemia and inflammation.