Anti-VEGFR2 F(ab') drug conjugate promotes renal accumulation and glomerular repair in diabetic nephropathy.

Poor renal distribution of antibody-based drugs is the key factor contributing to low treatment efficiency for renal diseases and side effects. Here, we prepare F(ab') fragmented vascular endothelial growth factor receptor 2 antibody (anti-VEGFR2 (F(ab')) to block VEGFR2 overactivation in diabetic nephropathy (DN). We find that the anti-VEGFR2 F(ab') has a higher accumulation in DN male mice kidneys than the intact VEGFR2 antibody, and simultaneously preserves the binding ability to VEGFR2. Furthermore, we develop an antibody fragment drug conjugate, anti-VEGFR2 F(ab')-SS31, comprising the anti-VEGFR2 F(ab') fragment linked to the mitochondria-targeted antioxidant peptide SS31. We find that introduction of SS31 potentiates the efficacy of anti-VEGFR2 F(ab'). These findings provide proof of concept for the premise that antibody fragment drug conjugate improves renal distribution and merits drug validation in renal disease therapy.