8FGX

Cryo-EM structure of the STAR-0215 Fab in complex with active human plasma kallikrein

Summary for 8FGX

• Entry DOI: 10.2210/pdb8fgx/pdb
• EMDB information: 29077
• Descriptor: STAR-0215 Light chain, STAR-0215 Heavy chain, Plasma kallikrein light chain, ... (4 entities in total)
• Functional Keywords: plasma kallikrein, plasma prekallikrein, fletcher factor, hereditary angioedema, hae, kininogenin, c1-inh, bradykinin, hydrolase-immune system complex, hydrolase/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 117240.32

Authors

Fuller, J.R.,Biris, N.,Bista, P. (deposition date: 2022-12-13, release date: 2023-09-06, Last modification date: 2024-10-23)

Primary citation

Bedian, V.,Biris, N.,Omer, C.,Chung, J.K.,Fuller, J.,Dagher, R.,Chandran, S.,Harwin, P.,Kiselak, T.,Violin, J.,Nichols, A.,Bista, P.
STAR-0215 is a Novel, Long-Acting Monoclonal Antibody Inhibitor of Plasma Kallikrein for the Potential Treatment of Hereditary Angioedema.
J.Pharmacol.Exp.Ther., 387:214-225, 2023

PubMed Abstract: Hereditary angioedema (HAE) is a rare autosomal dominant disorder caused by a deficiency in functional C1 esterase inhibitor, a serpin family protein that blocks the activity of plasma kallikrein. Insufficient inhibition of plasma kallikrein results in the overproduction of bradykinin, a vasoactive inflammatory mediator that produces both pain and unpredictable swelling during HAE attacks, with potentially life-threatening consequences. We describe the generation of STAR-0215, a humanized IgG1 antibody with a long circulating half-life (t) that potently inhibits plasma kallikrein activity, with a >1000-fold lower affinity for prekallikrein and no measurable inhibitory activity against other serine proteases. The high specificity and inhibitory effect of STAR-0215 is demonstrated through a unique allosteric mechanism involving N-terminal catalytic domain binding, destabilization of the activation domain, and reversion of the active site to the inactive zymogen state. The YTE (M252Y/S254T/T256E) modified fragment crystallizable (Fc) domain of STAR-0215 enhances pH-dependent neonatal Fc receptor binding, resulting in a prolonged t in vivo (∼34 days in cynomolgus monkeys) compared with antibodies without this modification. A single subcutaneous dose of STAR-0215 (≥100 mg) was predicted to be active in patients for 3 months or longer, based on simulations using a minimal physiologically based pharmacokinetic model. These data indicate that STAR-0215, a highly potent and specific antibody against plasma kallikrein with extended t, is a potential agent for long-term preventative HAE therapy administered every 3 months or less frequently. SIGNIFICANCE STATEMENT: STAR-0215 is a YTE-modified immunoglobulin G1 monoclonal antibody with a novel binding mechanism that specifically and potently inhibits the enzymatic activity of plasma kallikrein and prevents the generation of bradykinin. It has been designed to be a long-lasting prophylactic treatment to prevent attacks of HAE and to decrease the burden of disease and the burden of treatment for people with HAE.

PubMed: 37643795
DOI: 10.1124/jpet.123.001740

Experimental method

ELECTRON MICROSCOPY (2.62 Å)