Abstract: The present invention provides isolated and purified polynucleotides, polypeptides, and antibodies related to mammalian (e.g., mouse and human) legumain and the novel legumain splice variant, ZB-1. The invention further relates to the use of these isolated and purified polynucleotides, polypeptides, and antibodies, as well as other legumain and ZB-1 agonists and antagonists, in modulating legumain and/or ZB-1 activity, expression, and/or secretion in a cell or cell population, e.g., monocytes, macrophages, foam cells, vascular endothelial cells, kidney proximal tubule cells, arterial endothelial cells, sites of inflammatory cell invasion into a vessel intima, and neointimal lesional areas of an artery. The invention also provides legumain and ZB-1 antagonists, e.g., antagonistic small molecules, antibodies and antibody fragments to legumain and ZB-1, legumain and ZB-1 inhibitory polypeptides, and legumain and ZB-1 inhibitory polynucleotides.