Omalizumab

*仅供医学专业人士阅读参考 详解EOS在哮喘2型炎症中的核心机制及靶向治疗进展。 呼吸系统疾病诊疗已迈入发展变革新阶段，临床治疗目标亦从传统的疾病症状控制，逐步向临床治愈与疾病修饰的高阶方向迈进。2023年多国发布的哮喘诊疗指南均将“临床治愈”确立为核心治疗目标，其定义为满足以下所有条件：部分临床控制期患者在生物靶向药物治疗或其他抗哮喘治疗后，无症状时长达到1年及以上，无急性发作，肺功能检测结果正常或基本正常，且无需口服糖皮质激素（OCS）治疗[1]；全球哮喘防治创议（Global Initiative for Asthma，GINA）亦于2024年明确提出，临床治愈（Clinical Remission）是哮喘患者可实现的长期治疗目标[2]。 生物制剂的研发与临床应用，为重度哮喘患者达成临床治愈目标提供了重要实践路径，也推动以嗜酸性粒细胞（eosinophil，EOS）为核心的2型炎症机制研究与靶向干预，成为当前哮喘治疗领域的重要研究与临床实践方向。在近期召开的学术会议中，上海交通大学医学院附属瑞金医院呼吸与危重症医学科周剑平教授围绕EOS在哮喘炎症发生发展中的作用机制及靶向治疗研究进展展开专题分享，本文对相关核心内容进行系统整理，供大家参考与交流。 EOS与IL-5：哮喘2型炎症发生发展的关键 哮喘2型炎症的发生发展存在六大关键病理环节，其中EOS的病理性激活为核心环节，白介素-5（interleukin-5，IL-5）是调控EOS的特异性关键细胞因子，二者协同作用，共同推动哮喘气道炎症的进展与气道重塑的发生[3]。 EOS作为哮喘2型炎症的核心效应细胞，其表达水平升高与哮喘患者的不良临床预后呈显著相关性。真实世界研究数据表明，EOS水平升高的重度哮喘患者，其急性发作风险升高88%[4]、死亡风险升高63%[5]，同时肺功能恶化及疾病严重程度进展的风险亦显著增加。 从作用机制分析，EOS浸润至气道组织后，若发生凋亡障碍，将在局部持续聚集并进一步浸润气道组织，同时分泌IL-4、IL-5、IL-13等细胞因子，以及细胞毒性分泌物、趋化因子、神经介质、脂类介质等多种生物活性介质；上述介质可诱导气道平滑肌细胞增殖、杯状细胞化生及黏液高分泌，进而引发气道高反应性，推动气道重塑甚至肺纤维化的发生发展，而EOS的持续性气道浸润，会使气道重塑逐步呈现不可逆的病理特征[3]。 EOS由造血干细胞来源、表达CD34与IL-5Rα的EOS祖细胞（eosinophil progenitor，EoP）分化发育而来，在转录因子的调控及IL-3、粒细胞-巨噬细胞集落刺激因子（granulocyte-macrophage colony-stimulating factor，GM-CSF）、IL-5等细胞因子的共同作用下，完成其成熟过程[6,7]。其中，IL-5作为调控EOS的核心细胞因子，在EOS的整个生命周期中均发挥关键调控作用。 在骨髓微环境中，IL-5可促进EOS祖细胞分化、成熟为功能性EOS；在血液循环与靶组织微环境中，IL-5能够调控EOS完成从骨髓向外周血及炎性组织的黏附、迁移与募集过程，并进一步促进EOS的活化与脱颗粒。同时，IL-5可通过其特异性受体IL-5Rα调控多种炎症细胞与气道结构细胞的生物学行为，包括调节先天淋巴细胞2型（ILC2）、调节性T细胞的活性，促进肥大细胞与EOS的相互作用，调控气道平滑肌细胞的功能活性，推动成纤维细胞的增殖与活化等，进而实现2型炎症反应的级联放大[6,7]。 哮喘2型炎症的靶向生物制剂：机制与研究进展 针对哮喘2型炎症的靶向生物制剂，其作用靶点主要聚焦于EOS及其上下游相关细胞因子，不同制剂的作用靶点与作用机制存在差异。目前临床应用较为广泛的靶向生物制剂包括抗IL-5Rα单克隆抗体、抗IL-5单克隆抗体、抗IL-4Rα单克隆抗体及抗IgE单克隆抗体，各类制剂在EOS的调控效能与作用特征方面各具差异。 抗IL-5Rα单克隆抗体 抗IL-5Rα单克隆抗体可直接靶向EOS表面的IL-5Rα受体，通过结合IL-5Rα，阻断IL-5与受体的相互作用，并通过抗体依赖的细胞介导的细胞毒性作用（antibody-dependent cell-mediated cytotoxicity，ADCC）直接诱导EOS凋亡，实现快速、持续的外周血及组织EOS清除[8]。临床研究数据显示，过去一年内≥2次急性加重，且接受中-高剂量吸入性糖皮质激素-长效β2受体激动剂（ICS-LABA）治疗，外周血EOS计数（blood eosinophil count，BEC）≥300个/μL的重度嗜酸性粒细胞性哮喘（SEA）患者（12-75岁）经抗IL-5Rα单克隆抗体治疗48周后，相较于安慰剂组，年化急性发作率降低了74%[9]。 抗IL-5单克隆抗体 抗IL-5单克隆抗体以IL-5为特异性作用靶点，通过特异性结合IL-5，阻断IL-5信号通路，抑制体内的EOS的生物活性并使其数量降低至正常水平，从而控制EOS所介导的炎症[1]。临床研究数据表明，年龄≥12岁，入组前接受含ICS治疗≥12个月、同时使用≥1种控制药物治疗，且有≥2次既往哮喘急性发作史的SEA患者，在接受抗IL-5单克隆抗体治疗52周后，其临床显著急性发作（CSEs）发生率较安慰剂组降低65%[10]。 抗IL-4Rα单克隆抗体 抗IL-4Rα单克隆抗体通过靶向抑制IL-4/IL-13信号通路的传导，间接调控EOS的生物学行为，可抑制外周血EOS向气道组织内的迁移过程。在接受抗IL-4Rα单克隆抗体治疗的哮喘患者中，可观察到其外周血EOS水平呈一过性升高的特征性表现。临床研究数据显示，抗IL-4Rα单克隆抗体治疗组中EOS水平升高的比例达14%，高于安慰剂组的1%[11]。基于该临床特征，全球哮喘防治创议（GINA）2025版指南目前不推荐将该类制剂应用于BEC≥1500个/μL的重度哮喘患者，而是建议对于使用高剂量ICS-LABA治疗仍无法控制的严重EOS或 2 型哮喘患者，或需要长期使用OCS维持治疗的患者，可作为附加治疗选择[12]。 抗IgE单克隆抗体 抗IgE单克隆抗体可通过特异性结合外周血中的游离IgE，减少靶细胞表面的细胞结合型IgE表达，进而降低炎性介质的释放并抑制过敏性炎症反应的发生发展[13]，其对EOS的调控为间接作用模式，临床主要应用于过敏性哮喘患者的靶向治疗。临床研究数据显示，该类制剂治疗后第32周，患者痰液EOS水平较基线呈轻度升高趋势，外周血EOS水平的绝对值无明显变化[14]。 *以上数据来自不同研究，请勿直接对比 小结 哮喘诊疗已迈入个体化精准治疗的新阶段，该诊疗模式的发展推动了学界对哮喘2型炎症调控机制的深入探索与阐释。EOS作为哮喘2型炎症的核心效应细胞，全程参与哮喘气道炎症进展、气道重塑等关键病理环节，亦是哮喘2型炎症靶向治疗的核心靶点之一。 生物制剂的研发与临床应用，为重度哮喘患者达成临床治愈目标提供了重要的临床实践路径，不同靶向生物制剂因作用靶点与调控机制的差异，在EOS的靶向调控效能与作用特征方面各具特点。未来，随着对EOS介导2型炎症的分子机制研究不断深入，以及靶向生物制剂的研发迭代与临床应用范围的持续拓展，哮喘的靶向治疗策略将更趋精准化与个体化，不仅有望进一步提升重度哮喘患者的临床获益，亦能为其他EOS相关2型炎症性气道疾病的诊疗提供新的研究思路与临床干预方向。 专家简介 周剑平 教授 博士、副主任医师 上海交通大学医学院附属瑞金医院呼吸与危重症医学科，（兼）瑞金医院无锡分院呼吸与危重症医学科主任、瑞金医院第五届青联理事会副会长 上海市医学会呼吸分会第十二届委员会青委副主委（兼）控烟学组副组长 上海市康复医学会第一届泛血管康复专业委员会委员 上海市中西医结合分会第一届呼吸技术专业委员会委员 上海市抗癌协会第二届肿瘤呼吸内镜专业委员会委员 参考文献： [1]中华医学会呼吸病学分会. 支气管哮喘防治指南（2024年版）. 中华结核和呼吸杂志，2025，48(03):208-248.  [2]GINA 2024. https://ginasthma.org/wp-content/uploads/2025/05/GINA-2024-strategy-report_24_05_22-WMSA.pdf. 截至2026年3月25日. [3]McBrien CN, Menzies-Gow A. The Biology of Eosinophils and Their Role in Asthma. Front Med (Lausanne). 2017;4:93.  [4]SL, Chiu KC, Ko HK, et al. Comparing Patient Characteristics, Clinical Outcomes, and Biomarkers of Severe Asthma Patients in Taiwan. Biomedicines. 2021;9(7):764.  [5]Tupper OD, Ulrik CS. Long-term predictors of severe exacerbations and mortality in a cohort of well-characterised adults with asthma. Respir Res. 2021;22(1):269.   [6]Travers J and Rothenberg ME. Eosinophils in mucosal immune responses. Mucosal Immunol. 2015;8:464-75 [7]Marichal T, Mesnil C, Bureau F. Homeostatic Eosinophils: Characteristics and Functions. Front Med (Lausanne). 2017;4:101.  [8]赖克方，武焱旻，罗壮，等. 本瑞利珠单抗治疗基线外周血嗜酸性粒细胞计数≥150/μl重度哮喘患者的疗效：临床Ⅲ期MIRACLE研究亚组分析. 中华结核和呼吸杂志，2025，48(10):928-936. [9]Lai K, Sun D, Dai R, et al. Benralizumab efficacy and safety in severe asthma: A randomized trial in Asia. Respir Med.  [10]R. Chen, L. Wei, Y. Dai, et al. Efficacy and Safety of Mepolizumab as an Add-on Therapy in Chinese Patients With Severe Eosinophilic Asthma: A Randomized, Double-Blind, Parallel Group Phase 3 Study [abstract]. Am J Respir Crit Care Med 2023;207:A4766.  [11]Yancopoulos GD, Teper A. Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma. N Engl J Med. 2018 Jun 28;378(26):2475-2485.  [12]GINA 2025. https://ginasthma.org/wp-content/uploads/2025/11/GINA-2025-Update-25_11_08-WMS.pdf. 截至2026年3月25日. [13]中华医学会呼吸病学分会哮喘学组. 奥马珠单抗治疗过敏性哮喘的中国专家共识（2021版）. 中华结核和呼吸杂志, 2022, 45(4): 341-354.  [14]Mukherjee M, Kjarsgaard M, Radford K, Huang C, Leigh R, Dorscheid DR, Lemiere C, Boulet LP, Waserman S, Martin J, Nair P. Omalizumab in patients with severe asthma and persistent sputum eosinophilia. Allergy Asthma Clin Immunol. 2019 Apr 3;15:21.   本文审稿专家：周剑平教授 本材料由阿斯利康提供，仅供医疗卫生专业人士进行医学科学交流，不用于推广目的。 审批编码： CN-180657       过期日期：2027-03-29 *“医学界”力求所发表内容专业、可靠，但不对内容的准确性做出承诺；请相关各方在采用或以此作为决策依据时另行核查 戳“阅读原文”，学习更多临床技能

Peanut bans at schools. EpiPen training at summer camps. Parents struggling to find an alternative to PB&J. The massive rise in food allergies transformed how many American children grow up. But a combination of better biological understanding, and a new use of an old drug, has opened up a potentially huge market in biopharma — and effective treatments for patients. It’s turned Xolair, a 23-year-old asthma medicine, into a blockbuster after it won expanded approval in 2024 to treat food allergies. Since then, sales of Xolair have jumped from under $2 billion annually to more than $4 billion. Cash has started flooding into startups, with Merida Biosciences , Excellergy and Poplar Therapeutics all emerging from stealth over the last 12 months, raising a combined $241 million in their respective Series A rounds. And big pharma is ready to engage, too. Already this year, GSK acquired RAPT Therapeutics for $1.9 billion upfront to get its allergy drug ozureprubart; Novartis, seeking to bridge the incoming Xolair cliff, bought out six-month-old Excellergy last week for up to $2 billion; and Regeneron has added allergic programs for food, cats and birch tree pollen as well. The resurgence suggests a clear and eager demand among patients and families for new treatments. If other companies can develop better and longer-lasting allergy drugs, profits should follow and patients should benefit. “Before there was more of a notion that you could avoid certain foods,” said Angelika Jahreis, Novartis’ global head of immunology development. “But now we understand how serious the consequences can be, how cumbersome it is, and how many patients have multi-allergy, allergic diseases, and that they cannot just avoid allergens.” In 2024, the CDC estimated about 18 million adults and four million children reported an allergy to at least one food. The burgeoning competition comes with an unusual circumstance: The first Xolair biosimilar hit the market last year, and more are expected to launch in 2026. Should the newer treatments work, they’d be competing against cheap generics rather than other prescription drugs. Next comes the hard part: The companies’ drugs need to succeed in clinical trials. Such an emphatic sales uptick since 2024 begs an important question: Why did Novartis and Genentech, the Roche subsidiary that originally co-developed Xolair, wait so long to seek approval in food allergy? The 20-year gap between Xolair’s approvals can be attributed first and most significantly to the FDA’s reluctance to expose children to severe allergic reactions, said Robert Wood, a professor of pediatric allergy and immunology at Johns Hopkins. In the early 2000s, such studies often involved exposing kids to peanuts to see how much allergen they could tolerate before having a serious reaction, a “challenge study” similar to how some vaccines are developed. “The FDA, at that point, made clear to them that a food challenge outcome would not ever get them an approval,” Wood said. It was too risky. That same year, Genentech canceled a food allergy study after two children in the trial apparently suffered severe responses while taking allergy tests, according to a Wall Street Journal report from the time. With the FDA’s position and the trial’s issues, the company’s leadership got “really cold feet,” Wood said. “They literally just lost interest in bringing [Xolair] forward for food allergy.” The tide started to turn in 2012, when Wood and his Johns Hopkins colleagues won an NIH grant to test Xolair in a challenge study for food allergy. The trial showed patients could tolerate significantly more exposure to peanuts after taking Xolair for six months. That NIH trial alleviated some of the FDA’s concerns over food challenge studies. Regulators then opened the door to approvals when, in 2020, a California biotech called Aimmune Therapeutics won FDA approval for its treatment Palforzia — described as a daily, oral immunotherapy to treat severe peanut allergies. “If you’re doing a study in cholesterol lowering, there’s a clear endpoint, right? For food allergy, there was no endpoint,” said Mike Dybbs, a partner at Samsara BioCapital, which invested in Excellergy. “I give Aimmune a lot of credit for working with the FDA to create a registration path.” Each dose of Palforzia contained 600 mg of peanut protein (equivalent to about two peanuts) and patients in the study had a 67% chance of avoiding a severe reaction. The company was quickly snapped up by Nestlé for $2.6 billion. This, plus Wood’s research, helped set the stage not only for Xolair’s food allergy approval but also for other companies looking to develop competitors. While companies were working through the regulatory issues, researchers were getting a much better understanding of the biology behind Xolair and allergies more broadly. Most food allergies occur when the body’s immune system mistakenly identifies an allergen as a foreign invader and activates an antibody called immunoglobulin E, or IgE, to attack it. IgE once played a pivotal role in humans’ defense against parasites, but now that most parasites are uncommon in the developed world, this activation can lead the immune system to overreact to everyday foods and airborne allergens. Originally approved for patients with allergic asthma, Xolair targets and binds to the free-flowing IgE circulating in the bloodstream, which causes the condition’s hallmark inflammation. Researchers and clinicians also realized Xolair’s cancer risk — its label included a warning for an increase in primary malignancies — was not as serious as originally thought. The biotechs that have emerged to create Xolair successors are also trying to leverage this biology. But they’re doing so with a range of approaches. Merida, which put together the biggest raise at $121 million in April 2025, wants its treatment to not only bind to free-flowing IgE, as Xolair does, but to degrade it quickly, producing a faster response, chief scientific officer Dario Gutierrez told Endpoints. “The half-life of IgE, naturally in patients, is a couple days. Xolair increases the half-life to [about] 20 days,” Gutierrez said. Merida, on the other hand, “is specifically trying to attach itself to the free-flowing IgE and then destroy it before it can be recycled.” Excellergy wants its drugs to also separate the IgE that’s already attached itself to certain white blood cells, theoretically making it more effective. Previously, this was considered undruggable and Excellergy only recently dosed its first human patients. Poplar’s treatment, meanwhile, is described as an IgE “depleter,” which uses an undisclosed “triple-action mechanism” to hit free-flowing IgE, prevent it from binding to white blood cells, and reduce its production. Phase 1 data are expected in the second half of this year. Regeneron’s food allergy program is lagging behind its cat and birch allergy drugs, but it’s shooting for a combination approach with the megablockbuster Dupixent, which targets a different mechanism than IgE in a wide variety of conditions. Companies also see an opportunity for drugs more similar to Xolair that can be dosed less frequently. That’s the thesis behind GSK’s acquisition of RAPT, whose program ozureprubart is currently in a Phase 2b study. If everything works out, data could come next year with a possible launch in 2031. “The thing we liked about a Xolair-like product and a longer-acting version is the absolute convenience it provides,” GSK’s global business development chief Chris Sheldon said. Despite the excitement, there is no guarantee any of these approaches will succeed. Preventatively treating food allergy has remained a challenge among the few companies that have attempted it. Alladapt Immunotherapeutics shut down in 2024 after it couldn’t find the cash to run a Phase 3 study for an experimental food allergy drug, despite its earlier success. In January 2024, Novartis terminated a Phase 3 ligelizumab trial in peanut allergy because of dosing challenges, and the drug no longer appears on the company’s pipeline webpage. And Palforzia will soon be coming off the market for reasons unrelated to its safety or effectiveness. But the toughest hurdle could be the entrance of Xolair biosimilars, with one already approved and more expected this year. Xolair’s current annual list price is as high as $60,000 , and generics will likely be cheaper. A true Xolair competitor probably won’t reach the market until RAPT’s predicted 2031 launch. The Merida, Excellergy, Poplar and Regeneron food allergy drugs don’t yet have launch timelines. And due to the unusual timing of the biosimilar competition, the newer drugs will need to show substantial improvements in both convenience and effectiveness over Xolair to be widely used, said Heath Lukatch, co-founder of Red Tree Venture Capital, which seeded Excellergy. “In order to compete against those biosimilars with a brand new product, that’s just going to be the ticket to play,” Lukatch said.