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Cryo-EM structure of the STAR-0215 Fab in complex with active human plasma kallikrein
Structural highlights
DiseaseKLKB1_HUMAN Defects in KLKB1 are the cause of prekallikrein deficiency (PKK deficiency) [MIM:612423; also known as Fletcher factor deficiency. This disorder is a blood coagulation defect. FunctionKLKB1_HUMAN The enzyme cleaves Lys-Arg and Arg-Ser bonds. It activates, in a reciprocal reaction, factor XII after its binding to a negatively charged surface. It also releases bradykinin from HMW kininogen and may also play a role in the renin-angiotensin system by converting prorenin into renin. Publication Abstract from PubMedHereditary 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(1/2)) 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(1/2) in vivo ( approximately 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(1/2), 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. STAR-0215 is a Novel, Long-Acting Monoclonal Antibody Inhibitor of Plasma Kallikrein for the Potential Treatment of Hereditary Angioedema.,Bedian V, Biris N, Omer C, Chung JK, Fuller J, Dagher R, Chandran S, Harwin P, Kiselak T, Violin J, Nichols A, Bista P J Pharmacol Exp Ther. 2023 Nov;387(2):214-225. doi: 10.1124/jpet.123.001740. Epub , 2023 Aug 29. PMID:37643795[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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