Antibody blocking the ZIP12 zinc importer curbs pulmonary artery cell remodeling and shows early clinical tolerability
- ZIP12 is a zinc importer elevated in remodeled pulmonary arterioles in PAH; raising it in human smooth muscle cells increased free intracellular zinc and drove proliferation, while knockdown eased disease in rodents.
- The humanized antibody APL-9796 restored zinc levels and dampened proliferation, cytoskeletal change and contractility in patient-derived fibroblasts, smooth muscle cells and engineered artery tissue.
- In humanized Slc39a12 rats it improved cardiopulmonary readouts in a dose-dependent way, and it was well tolerated in phase 1 studies; transcriptomics implicated AMPK, PPAR and PI3K-Akt pathways.
💡 Points
Upregulation in human tissue and rodent knockdown support ZIP12, but without human loss-of-function genetics the validity case stays correlative. The humanized rat is also a convenient fit for the antibody, and the readouts do not show how much ZIP12 is engaged in remodeled arterioles. Phase 1 tolerability is not efficacy, so the translational gap in PAH remains wide open.
Targeting ZIP12-mediated Zn2+ signaling as a treatment for pulmonary hypertension ↗