美国基因泰克公司Tangsheng Yi、Robert A. Lazarus和Joseph R. Arron等研究人员，合作制备出一种变构的抗类胰蛋白酶抗体可用于治疗肥大细胞介导的严重哮喘。这一研究成果于2019年10月3日发表在国际学术期刊《细胞》上。

研究人员发现肥大细胞类胰蛋白酶在重度哮喘患者中升高，而与2型生物标记物状态无关。活跃的β-类胰蛋白酶等位基因数量与血胰蛋白酶水平相关，并且携带更活跃等位基因的哮喘患者从抗IgE治疗中获益较少。研究人员制备了针对人β-类胰蛋白酶的非竞争性抑制抗体，该抗体可将活性四聚体解离为非活性单体。 β-类胰蛋白酶/抗体复合物的2.15Å晶体结构与生化研究相结合，揭示了四聚化所需的小界面和大界面的变构不稳定的分子基础。

该抗类胰蛋白酶抗体可在人源化小鼠模型中有效阻断类胰蛋白酶的酶促活性，减少IgE介导的全身过敏反应，并以有利的药代动力学抑制蛔虫敏感化的食蟹猴的气道类胰蛋白酶。这些数据为开发抗类胰蛋白酶作为严重哮喘的临床疗法提供了基础。

据悉，伴有低2型炎症的严重哮喘患者从靶向2型细胞因子的疗法中获得的临床益处较少，并且体现了潜在需求。

附：英文原文

Title: An Allosteric Anti-tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma

Author: Henry R. Maun, Janet K. Jackman, David F. Choy, Kelly M. Loyet, Tracy L. Staton, Guiquan Jia, Amy Dressen, Jason A. Hackney, Meire Bremer, Benjamin T. Walters, Rajesh Vij, Xiaocheng Chen, Neil N. Trivedi, Ashley Morando, Michael T. Lipari, Yvonne Franke, Xiumin Wu, Juan Zhang, John Liu, Ping Wu, Diana Chang, Luz D. Orozco, Erin Christensen, Manda Wong, Racquel Corpuz, Julie Q. Hang, Jeff Lutman, Siddharth Sukumaran, Yan Wu, Savita Ubhayakar, Xiaorong Liang, Lawrence B. Schwartz, Magda Babina, Prescott G. Woodruff, John V. Fahy, Rahul Ahuja, George H. Caughey, Aija Kusi, Mark S. Dennis, Charles Eigenbrot, Daniel Kirchhofer, Cary D. Austin, Lawren C. Wu, James T. Koerber, Wyne P. Lee, Brian L. Yaspan, Kathila R. Alatsis, Joseph R. Arron, Robert A. Lazarus, Tangsheng Yi

Issue&Volume: 2019/10/03

Abstract: Severe asthma patients with low type 2 inflammation derive less clinical benefit from therapies targeting type 2 cytokines and represent an unmet need. We show that mast cell tryptase is elevated in severe asthma patients independent of type 2 biomarker status. Active β-tryptase allele count correlates with blood tryptase levels, and asthma patients carrying more active alleles benefit less from anti-IgE treatment. We generated a noncompetitive inhibitory antibody against human β-tryptase, which dissociates active tetramers into inactive monomers. A 2.15 crystal structure of a β-tryptase/antibody complex coupled with biochemical studies reveal the molecular basis for allosteric destabilization of small and large interfaces required for tetramerization. This anti-tryptase antibody potently blocks tryptase enzymatic activity in a humanized mouse model, reducing IgE-mediated systemic anaphylaxis, and inhibits airway tryptase in Ascaris-sensitized cynomolgus monkeys with favorable pharmacokinetics. These data provide a foundation for developing anti-tryptase as a clinical therapy for severe asthma.

DOI: 10.1016/j.cell.2019.09.009

Source: https://www.cell.com/cell/fulltext/S0092-8674(19)31015-3