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

Abstract

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. Transforming growth factor β (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 αvβ8 integrin in renal fibrosis and its potential as a therapeutic target in CKD. We used various preclinical models of CKD, including humanized αvβ8 mice and the db/db uninephrectomy model, to investigate the role of αvβ8 integrin in renal fibrosis. Gene Set Variation Analysis (GSVA) was employed to assess fibrotic gene signatures in human kidney biopsies. The therapeutic potential of MEDI8367, a monoclonal antibody targeting αvβ8 integrin, was evaluated in vitro and in vivo.

Results: Our findings demonstrate that αvβ8 integrin is upregulated in the tubulointerstitium of CKD kidneys, particularly in diabetic kidney disease (DKD), and correlates with TGF-β activation and renal function decline. MEDI8367 effectively inhibited αvβ8-mediated TGF-β activation in vitro and attenuated murine unilateral ureteral obstruction (UUO)-induced renal fibrosis. Notably, inhibition of αvβ8 reduced kidney damage and improved kidney function in models of DKD 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.