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タイトル | STAR-0215 is a Novel, Long-Acting Monoclonal Antibody Inhibitor of Plasma Kallikrein for the Potential Treatment of Hereditary Angioedema. |
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ジャーナル・号・ページ | J Pharmacol Exp Ther, Vol. 387, Issue 2, Page 214-225, Year 2023 |
掲載日 | 2023年8月29日 |
著者 | Vahe Bedian / Nikolaos Biris / Charles Omer / Jou-Ku Chung / James Fuller / Rafif Dagher / Sachin Chandran / Peter Harwin / Tomas Kiselak / Jonathan Violin / Andrew Nichols / Pradeep Bista / |
PubMed 要旨 | 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. ...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. |
リンク | J Pharmacol Exp Ther / PubMed:37643795 |
手法 | EM (単粒子) |
解像度 | 2.62 Å |
構造データ | EMDB-29077, PDB-8fgx: |
化合物 | ChemComp-NAG: |
由来 |
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キーワード | HYDROLASE/IMMUNE SYSTEM / plasma kallikrein / Plasma prekallikrein / Fletcher factor / hereditary angioedema / HAE / Kininogenin / C1-INH / Bradykinin / HYDROLASE-IMMUNE SYSTEM complex |