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Targeting α v β 8 Integrin with mAb MEDI8367 Prevents Fibrosis in Preclinical Models of CKD
Elena Liarte Marin1, Asha Seth1, Lihuan Liang1
1Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca.
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.
Insights
Targeting alpha-v-beta-8 (αvβ8) integrin with MEDI8367 shows promise for treating chronic kidney disease (CKD). This approach inhibits fibrosis and improves kidney function, offering a new therapeutic avenue for CKD patients.
Area of Science:
- Nephrology
- Integrin Biology
- Fibrosis Research
Background:
- Chronic kidney disease (CKD) is a significant global health concern, driven by increasing rates of diabetes and obesity.
- Renal fibrosis, marked by extracellular matrix accumulation, is a key driver of CKD progression.
- Transforming growth factor beta (TGF-β) is a critical profibrotic cytokine, but its systemic inhibition is limited by toxicity.
Purpose of the Study:
- To investigate the role of alpha-v-beta-8 (αvβ8) integrin in renal fibrosis.
- To evaluate αvβ8 integrin as a potential therapeutic target for CKD.
- To assess the efficacy of MEDI8367, an αvβ8-targeting antibody, in preclinical CKD models.
Main Methods:
- Utilized preclinical CKD models, including humanized αvβ8 mice and db/db uninephrectomy models.
- Employed Gene Set Variation Analysis (GSVA) to analyze fibrotic gene signatures in human kidney biopsies.
- Evaluated MEDI8367's therapeutic potential in vitro and in vivo.
Main Results:
- αvβ8 integrin was found to be upregulated in CKD kidneys, correlating with TGF-β activation and declining renal function.
- MEDI8367 effectively inhibited αvβ8-mediated TGF-β activation and attenuated renal fibrosis in vivo.
- Inhibition of αvβ8 reduced kidney damage and improved function in models of diabetic kidney disease and hypertensive nephropathy.
Conclusions:
- αvβ8 integrin inhibition presents a novel therapeutic strategy for mitigating renal fibrosis in CKD.
- MEDI8367 demonstrates potential to improve kidney function and offers a complementary approach to existing CKD treatments.
