STAR-0215 is a Novel, Long-Acting Monoclonal Antibody Inhibitor of Plasma Kallikrein for the Potential Treatment of Hereditary Angioedema

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

doi:10.1124/jpet.123.001740

STAR-0215 is a Novel, Long-Acting Monoclonal Antibody Inhibitor of Plasma Kallikrein for the Potential Treatment of Hereditary Angioedema

J Pharmacol Exp Ther. 2023 Nov;387(2):214-225. doi: 10.1124/jpet.123.001740. Epub 2023 Aug 29.

Authors

Affiliations

¹ Quellis Biosciences, Waltham, Massachusetts (V.B., C.O., P.H., T.K., J.V.); Astria Therapeutics, Inc., Boston, Massachusetts (N.B., C.O., J.K.C., R.D., S.C., J.V., A.N., P.B.); and Helix Biostructures, Indianapolis, Indiana (J.F.).
² Quellis Biosciences, Waltham, Massachusetts (V.B., C.O., P.H., T.K., J.V.); Astria Therapeutics, Inc., Boston, Massachusetts (N.B., C.O., J.K.C., R.D., S.C., J.V., A.N., P.B.); and Helix Biostructures, Indianapolis, Indiana (J.F.) nbiris@astriatx.com.

PMID: 37643795
DOI: 10.1124/jpet.123.001740

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_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 (∼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.