Structure of STAR-0215 Bound to Active Plasma Kallikrein Reveals a Novel Mechanism of Enzyme Inhibition

Inhibition of plasma kallikrein (pKal) activity is a validated mechanism for prevention of hereditary angioedema (HAE) attacks. High potency and long duration of action are key drivers of prophylactic efficacy of pKal inhibitors. STAR-0215 is a novel, potent and selective long-acting monoclonal antibody plasma kallikrein pKal inhibitor in clinical development. In monkeys dosed subcutaneously, STAR-0215 inhibits pKal activity rapidly and durably. We investigated STAR-0215 structure and binding to pKal and its inhibitory mechanism of action by utilizing Hydrogen/Deuterium Exchange Mass Spectrometry (HDX-MS) and Cryogenic Electron Microscopy (Cryo-EM).