Work

Targeting αvβ8 Integrin with mAb MEDI8367 Prevents Fibrosis in Preclinical Models of CKD

Year: 2025

Type: article

Abstract: KEY POINTS: α v β 8 integrin was upregulated in kidney tubules and associated with fibrosis and reduced kidney function in human CKD. MEDI8367 blocked α v β 8-mediated TGFβ activation and reduced fibrosis in mouse unilateral ureteral obstruction model. In diabetic kidney disease mouse models, α v β 8 inhibition improved kidney injury markers and preserved kidney function. BACKGROUND: CKD is a global health issue exacerbated by the rising prevalence of diabetes and obesity. Renal fibrosis, characterized by the accumulation of extracellular matrix proteins, is a critical factor in CKD progression. TGF- β , a key profibrotic cytokine, plays a pivotal role in this process. However, systemic inhibition of TGF- β has been limited by associated toxicities. METHODS: This study explores the role of α v β 8 integrin in renal fibrosis and its potential as a therapeutic target in CKD. We used various preclinical models of CKD, including humanized α v β 8 mice and the db/db uninephrectomy model, to investigate the role of α v β 8 integrin in renal fibrosis. Gene set variation analysis was used to assess fibrotic gene signatures in human kidney biopsies. The therapeutic potential of MEDI8367, a monoclonal antibody targeting α v β 8 integrin, was evaluated in vitro and in vivo . RESULTS: Our findings demonstrate that α v β 8 integrin is upregulated in the tubulointerstitium of CKD kidneys, particularly in diabetic kidney disease, and correlates with TGF- β activation and renal function decline. MEDI8367 effectively inhibited α v β 8-mediated TGF- β activation in vitro and attenuated murine unilateral ureteral obstruction-induced renal fibrosis. Notably, inhibition of α v β 8 reduced kidney damage and improved kidney function in models of diabetic kidney disease and hypertensive nephropathy. CONCLUSIONS: Our study highlights the potential of MEDI8367 to mitigate renal fibrosis and improve kidney function, offering a novel approach to CKD treatment that complements existing therapies.

Source: Kidney360

DOI: 10.34067/kid.0000001006