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Fibrotic remodeling is the primary driver of functional loss in chronic kidney disease, with no specific anti-fibrotic agent available for clinical use. Transglutaminase 2 (TG2), a wound response enzyme that irreversibly crosslinks extracellular matrix proteins causing dysregulation of extracellular matrix turnover, is a well-characterized anti-fibrotic target in the kidney. We describe the humanization and characterization of two anti-TG2 monoclonal antibodies (zampilimab hDC1/UCB7858 and BB7) that inhibit crosslinking by TG2 in human in vitro and rabbit/cynomolgus monkey i n vivo models of chronic kidney disease. Determination of zampilimab half-maximal inhibitory concentration (IC 50 ) against recombinant human TG2 was undertaken using the KxD assay and determination of dissociation constant (K d ) by surface plasmon resonance. Efficacy in vitro was established using a primary human renal epithelial cell model of tubulointerstitial fibrosis, to assess mature deposited extracellular matrix proteins. Proof of concept in vivo used a cynomolgus monkey unilateral ureteral obstruction model of chronic kidney disease. Zampilimab inhibited TG2 crosslinking transamidation activity with an IC 50 of 0.25 nM and K d of 50%, with no safety signals. Our data support the clinical investigation of zampilimab for the treatment of kidney fibrosis.
Huang et al. (Thu,) studied this question.