Article Alert: An anti-VEGFR2 F(ab')2 Drug Conjugate as a Therapeutic Agent for Diabetic Nephropathy

Diabetic nephropathy (DN) is a common complication of diabetes mellitus types 1 and 2, frequently leading to end-stage renal disease. An important molecular event associated with DN progression is the overactivation of glomerular vascular endothelial growth factor receptor 2 (VEGFR2) that contributes to the development of albuminuria, one of the hallmarks of kidney decompensation. For this reason, specific targeting of VEGFR2 in the kidneys with monoclonal antibodies (mAbs) has attracted attention as a possible therapy for DN. Unfortunately, the molecular size of standard IgG-format mAbs prevents functional accumulation in the kidneys, resulting in poor bioavailability and a problematic side effect profile.

A new study by Liu et al. describes a novel strategy to improve the efficacy of VEGFR2 monoclonal antibody-based treatment (1). To reduce the antibody's molecular weight, the authors generated the F(ab')₂ fragment of a VEGFR2 mAb known to inhibit receptor activity. Using normal and DN mouse models, they showed increased accumulation of fluorescently labeled anti-VEGFR2 F(ab')₂ in the DN mouse kidneys. They then conjugated this construct to SS31, a mitochondria-targeted peptide with antioxidant properties that has shown promise in various renal disorders involving mitochondrial dysfunction. Performing a series of analyses and assays, the researchers found the anti-VEGFR2 F(ab')₂ fragment alone exerted positive effects on glomerular structure, inflammatory markers, and fibrosis in the DN mouse model. However, the SS31 conjugate offered the additional benefit of decreasing mitochondrial oxidative stress, a known component of DN progression. This work by Liu et al. establishes an intriguing framework for further research into antibody- and antibody-drug conjugate (ADC)-focused therapies for renal disease.

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