Targeting α v β 8 Integrin with mAb MEDI8367 Prevents Fibrosis in Preclinical Models of CKD.

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.