BioCentury
ARTICLE | Distillery Therapeutics

Inflammation; dermatology; renal

January 3, 2017 11:07 PM UTC

Cell culture, human sample and mouse studies identified anti-P2RX7 nanobodies that could help treat allergic contact dermatitis, glomerulonephritis and other inflammatory diseases. Screening of nanobody libraries from P2RX7-immunized llamas, engineering of hits to fuse them to an albumin-targeting domain, and testing of the engineered nanobodies in cell-based activity assays yielded one compound that inhibited mouse P2RX7 with an IC50 of 1.6 nM and another that inhibited human P2RX7 with an IC50 of 0.2 nM. In human blood pretreated with lipopolysaccharide (LPS), the nanobody against human P2RX7 decreased levels of the inflammatory cytokine IL-1β compared with two P2RX7 inhibitor tool compounds. In a mouse model of allergic contact dermatitis of the ear, the nanobody against mouse P2RX7 decreased ear weight - a marker of local inflammation - and ear levels of the inflammatory cytokines IL-6 and IL-1β compared with an engineered control nanobody. In a mouse model of experimental glomerulonephritis, the nanobody against mouse P2RX7 decreased urine levels of albumin and pro-inflammatory monocyte chemoattractant protein-1 (MCP-1; CCL2), serum levels of IL-6, markers of kidney damage and the development of nephrotic syndrome. Next steps could include testing the nanobodies in additional models of inflammation.

Evotec AG and Zhejiang Conba Pharmaceutical Co. Ltd. have the P2RX7 antagonist EVT401 in Phase II testing for inflammation and Phase I testing for rheumatoid arthritis...