Fostamatinib Disodium

Third quarter 2025 total revenue of approximately $69.5 million, including record net product sales of $64.1 million and contract revenues from collaborations of $5.4 million Generated $27.9 million of net income in the third quarter of 2025 Completed enrollment in the dose escalation phase and enrolled the first patient in the dose expansion phase of the ongoing Phase 1b study evaluating R289, Rigel's dual IRAK1/4 inhibitor, in lower-risk MDS Oral presentation featuring updated data from the dose escalation phase of the R289 Phase 1b study to be presented at the ASH Annual Meeting in December Updated 2025 Outlook: Total revenue of approximately $285 to $290 million, which includes net product sales of $225 to $230 million Conference call and webcast scheduled today at 4:30 p.m. Eastern Time SOUTH SAN FRANCISCO, Calif., Nov. 4, 2025 /PRNewswire/ -- Rigel Pharmaceuticals, Inc. (Nasdaq: RIGL), a commercial stage biotechnology company focused on hematologic disorders and cancer, today reported financial results for the third quarter ended September 30, 2025, including sales of TAVALISSE® (fostamatinib disodium hexahydrate), GAVRETO® (pralsetinib) and REZLIDHIA® (olutasidenib), and recent business progress. "Our strong third-quarter performance demonstrates our strategic focus on commercial execution, pipeline development, and financial discipline. We are raising our full-year 2025 guidance due to our outstanding commercial performance year-to-date," said Raul Rodriguez, Rigel's president and CEO. "Our development pipeline continues to advance, including our ongoing Phase 1b study evaluating R289 for the treatment of patients with lower-risk MDS. With enrollment complete in the dose escalation phase of the study, we look forward to presenting updated data in an oral presentation at ASH in December. We're also excited to have reached the next milestone of this program with the initiation of the dose expansion phase of the study." Third Quarter 2025 Business Update Commercial Net product sales were $64.1 million, an increase of 65% from the same period of 2024. TAVALISSE was commercially launched in South Korea in July by JW Pharmaceutical Corporation, the licensing partner of Kissei Pharmaceutical Co., Ltd. (Kissei), Rigel's partner in certain Asian countries. Clinical Development Rigel continues to advance its Phase 1b clinical study evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy of R2891, a potent and selective dual interleukin receptor-associated kinases 1 and 4 (IRAK1/4) inhibitor, in patients with relapsed or refractory (R/R) lower-risk myelodysplastic syndrome (MDS). Enrollment in the dose escalation phase of the study was completed in July. In October, Rigel announced the first patient was enrolled in the dose expansion phase of the study, where up to 40 patients will be randomized to either 500 mg once daily or 500 mg twice daily to determine the recommended Phase 2 dose for future clinical trials. Rigel announced one oral presentation and four poster presentations highlighting data from its commercial and clinical-stage hematology and oncology portfolio at the upcoming 67th American Society of Hematology (ASH) Annual Meeting and Exposition. The abstract with updated data from the ongoing Phase 1b study of R289 showed R289 continues to be generally well tolerated in a heavily pretreated lower-risk MDS patient population, the majority of whom were high transfusion burden at study entry, and preliminary signs of efficacy in dose levels of at least 500 mg once daily and higher. Updated data as of an October 28, 2025, data cut off will be presented in the oral presentation. The company will also present additional data for olutasidenib in patients with R/R mutated isocitrate dehydrogenase-1 (mIDH1) acute myeloid leukemia (AML). The fifth study under the strategic alliance between Rigel and The University of Texas MD Anderson Cancer Center opened for enrollment in September. This Phase 2 multi-arm, multi-center, open-label, non-randomized clinical study will evaluate olutasidenib in combination with co-targeted therapies in patients with R/R IDH1-mutated myeloid malignancies harboring activated signaling pathway mutations (NCT07032727). The primary objectives of the study are to evaluate safety and the composite complete remission rate. In October, the first patient was enrolled in the CONNECT Phase 2 TarGeT-D study evaluating olutasidenib in combination with temozolomide, followed by olutasidenib monotherapy as a maintenance regimen for newly-diagnosed adolescent and young adult patients with a high-grade glioma harboring an IDH1 mutation (NCT06161974). Corporate Eli Lilly and Company (Lilly) continues to advance ocadusertib (previously R552 or LY3871801), an investigational, potent and selective receptor-interacting protein kinase 1 (RIPK1) inhibitor. Enrollment in the Phase 2a clinical trial in adult patients with moderately to severely active rheumatoid arthritis is ongoing. Rigel will continue to be entitled to receive milestones and tiered royalty payments on future net sales of ocadusertib. In early October, Rigel received notification from Lilly that it will terminate the central nervous system (CNS) disease program related to the collaboration between the two companies, which will become effective 60 days following notification. Third Quarter 2025 and Year-to-Date Financial Update For the third quarter ended September 30, 2025, total revenues were $69.5 million, consisting of $64.1 million in net product sales and $5.4 million in contract revenues from collaborations. Net product sales grew 65% compared to $38.9 million in the same period of 2024. TAVALISSE net product sales were $44.7 million, growth of 70% compared to $26.3 million in the same period of 2024. GAVRETO net product sales were $11.1 million, growth of 56% compared to $7.1 million in the same period of 2024. REZLIDHIA net product sales were $8.3 million, growth of 50% compared to $5.5 million in the same period of 2024. Contract revenues from collaborations primarily consisted of $3.1 million of revenue from Grifols S.A. (Grifols) related to delivery of drug supplies and earned royalties, $1.8 million of revenue from Kissei related to the delivery of drug supplies, and $0.2 million of revenue from Medison Pharma (Medison) related to delivery of drug supplies and earned royalties. Total costs and expenses were $41.0 million compared to $41.3 million for the same period of 2024. The decrease in costs and expenses was mainly due to lower cost of product sales, as the prior period included a sublicensing fee. This decrease was partially offset by increased research and development costs driven by the timing of clinical activities related to olutasidenib and R289 and higher personnel-related costs. Rigel reported net income of $27.9 million, or $1.55 basic and $1.46 diluted per share, compared to $12.4 million, or $0.71 basic and $0.70 diluted per share, for the same period of 2024. For the nine months ended September 30, 2025, total revenues were $224.5 million, consisting of $166.6 million in net product sales and $57.9 million in contract revenues from collaborations. Net product sales grew 69% compared to $98.4 million in the same period of 2024. TAVALISSE net product sales were $113.3 million, growth of 54% compared to $73.8 million in the same period of 2024. GAVRETO net product sales were $31.9 million, growth of 252% compared to $9.0 million in the same period of 2024. GAVRETO became commercially available from Rigel in late June 2024. REZLIDHIA net product sales were $21.4 million, growth of 38% compared to $15.6 million in the same period of 2024. Contract revenues from collaborations primarily consisted of $40.0 million in non-cash revenue resulting from the release of the remaining cost share liability related to the agreement with Lilly for the development and commercialization of ocadusertib, $9.9 million of revenue from Grifols related to delivery of drug supplies and earned royalties, $6.9 million of revenue from Kissei related to a milestone payment and delivery of drug supplies and $0.8 million of revenue from Medison related to delivery of drug supplies and earned royalties. Total costs and expenses were $122.2 million compared to $114.1 million for the same period of 2024. The increase in costs and expenses was mainly due to higher cost of product sales, increased research and development costs driven by the timing of clinical activities related to olutasidenib and R289, and higher personnel-related costs. Rigel reported net income of $99.0 million, or $5.52 basic and $5.38 diluted per share, compared to $3.1 million, or $0.18 basic and diluted per share, for the same period of 2024. Cash, cash equivalents and short-term investments as of September 30, 2025 was $137.1 million, compared to $77.3 million as of December 31, 2024. 2025 Outlook Rigel is updating its 2025 total revenue guidance to approximately $285 to $290 million, an increase from the previous range of approximately $270 to $280 million, which includes: Net product sales of approximately $225 to $230 million, an increase from the previous range of approximately $210 to $220 million. Contract revenues from collaborations of approximately $60 million. The company anticipates it will report positive net income for the full year 2025, while funding existing and new clinical development programs. Conference Call and Webcast with Slides Today at 4:30pm Eastern Time Rigel will hold a live conference call and webcast today at 4:30pm Eastern Time (1:30pm Pacific Time). Participants can access the live conference call by dialing (877) 407-3088 (domestic) or (201) 389-0927 (international). The conference call will also be webcast live and can be accessed from the Investor Relations section of the company's website at . The webcast will be archived and available for replay after the call via the Rigel website. About ITP In patients with immune thrombocytopenia (ITP), the immune system attacks and destroys the body's own blood platelets, which play an active role in blood clotting and healing. Common symptoms of ITP are excessive bruising and bleeding. Patients suffering with chronic ITP may live with an increased risk of severe bleeding events that can result in serious medical complications or even death. Current therapies for ITP include steroids, blood platelet production boosters (TPO-RAs), and splenectomy. However, not all patients respond to existing therapies. As a result, there remains a significant medical need for additional treatment options for patients with ITP. About NSCLC It is estimated that over 226,000 adults in the U.S. will be diagnosed with lung cancer in 2025. Lung cancer is the leading cause of cancer death in the U.S, with non-small cell lung cancer (NSCLC) being the most common type accounting for 85-90% of all lung cancer diagnoses.2 RET fusions are implicated in approximately 1-2% of patients with NSCLC.3 About AML Acute myeloid leukemia (AML) is a rapidly progressing cancer of the blood and bone marrow that affects myeloid cells, which normally develop into various types of mature blood cells. AML occurs primarily in adults and accounts for about 1 percent of all adult cancers. The American Cancer Society estimates that there will be about 22,010 new cases in the United States, most in adults, in 2025.4 Relapsed AML affects about half of all patients who, following treatment and remission, experience a return of leukemia cells in the bone marrow.5,6 Refractory AML, which affects between 10 and 40 percent of newly diagnosed patients, occurs when a patient fails to achieve remission even after intensive treatment.7 Quality of life declines for patients with each successive line of treatment for AML, and well-tolerated treatments in relapsed or refractory disease remain an unmet need. About TAVALISSE® TAVALISSE (fostamatinib disodium hexahydrate) tablets is indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. Please click here for Important Safety Information and Full Prescribing Information for TAVALISSE. About GAVRETO® GAVRETO is indicated for the treatment of adult patients with metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA-approved test and adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).* *Thyroid indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). Please click here for Important Safety Information and Full Prescribing Information for GAVRETO. About REZLIDHIA® REZLIDHIA is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test. Please click here for Important Safety Information and Full Prescribing Information, including Boxed WARNING, for REZLIDHIA. To report side effects of prescription drugs to the FDA, visit or call 1-800-FDA-1088 (800-332-1088). TAVALISSE, GAVRETO and REZLIDHIA are registered trademarks of Rigel Pharmaceuticals, Inc. About Rigel Rigel Pharmaceuticals, Inc. (Nasdaq: RIGL) is a biotechnology company dedicated to discovering, developing and providing novel therapies that significantly improve the lives of patients with hematologic disorders and cancer. Founded in 1996, Rigel is based in South San Francisco, California. For more information on Rigel, the Company's marketed products and pipeline of potential products, visit . R289 is an investigational compound not approved by the FDA. The American Cancer Society. Key Statistics for Lung Cancer. Revised January 16, 2025. Accessed September 30, 2025: Kato, S. et al. RET Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients. Clin Cancer Res. 2017;23(8):1988-1997 doi: 10.1158/1078-0432.CCR-16-1679 The American Cancer Society. Key Statistics for Acute Myeloid Leukemia (AML). Revised March 4, 2025. Accessed September 30, 2025: Patel, A, et al. Outcomes of Patients With Acute Myeloid Leukemia Who Relapse After 5 Years of Complete Remission. 2021 Sep 7;28(7):811-814. doi: Thol F, Ganser, A. Treatment of Relapsed Acute Myeloid Leukemia. Curr. Treat. Options on Oncol. (2020) 21: 66. doi: Thol F, Schlenk RF, Heuser M, Ganser A. How I treat refractory and early relapsed acute myeloid leukemia. Blood (2015) 126 (3): 319-27. doi: Forward Looking Statements Thi s press release contains forward-looking statements relating to, among other things, expected commercial and financial results, increased projections of financial performance and outlook for 2025, expectations for growing our commercial business , continued enrollment of our R289 study, presentation of study data, development of ocadusertib, expectation of clinical outcomes, continued ability for developing and commercializing TAVALISSE, GAVRETO, and REZLIDHIA domestically and in certain international markets, and expectations for Rigel's partnering and collaboration efforts. Any statements contained in this press release that are not statements of historical fact may be deemed to be forward-looking statements. Forward-looking statements can be identified by words such as "anticipates", "plan", "outlook", "potential", "may", "look to", "expects", "will", "initial", "promising", and similar expressions in reference to future periods. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based on Rigel's current beliefs, expectations, and assumptions and hence they inherently involve significant risks, uncertainties and changes in circumstances that are difficult to predict and many of which are outside of our control. Therefore, you should not rely on any of these forward-looking statements. Actual results and the timing of events could differ materially from those anticipated in such forward looking statements as a result of these risks and uncertainties, which include, without limitation, risks and uncertainties associated with the commercialization and marketing of fostamatinib, olutasidenib and pralsetinib; risks that the FDA, European Medicines Agency, PMDA or other regulatory authorities may make adverse decisions regarding fostamatinib, pralsetinib, ocadusertib or olutasidenib; risks that clinical trials may not be predictive of real-world results or of results in subsequent clinical trials; risks that fostamatinib, pralsetinib, ocadusertib or olutasidenib may have unintended side effects, adverse reactions or incidents of misuses; the availability of resources to develop Rigel's product candidates; market competition; as well as other risks detailed from time to time in Rigel's reports filed with the Securities and Exchange Commission, including its Quarterly Report on Form 10-Q for the quarter ended June 30, 2025 and subsequent filings. Any forward-looking statement made by us in this press release is based only on information currently available to us and speaks only as of the date on which it is made. Rigel does not undertake any obligation to update forward-looking statements, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise, and expressly disclaims any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein, except as required by law. Contact for Investors & Media: Investors: Rigel Pharmaceuticals, Inc. 650.624.1232 [email protected] Media: David Rosen Argot Partners 646.461.6387 [email protected] SOURCE Rigel Pharmaceuticals, Inc. 21% more press release views with Request a Demo

抗体介导的排斥反应的治疗标准 Georg A Böhmig1, Maarten Naesens2, Ondrej Viklicky3, Olivier Thaunat4, Matthias Diebold5, Lionel Rostaing6, Klemens Budde7 摘要 抗体介导排斥反应(AMR)仍是导致移植物功能丧失的主要原因，造成显著的健康与经济负担。尽管该机制早在25年前就被发现，但AMR治疗至今仍无统一标准，且尚未有疗法获得权威监管机构的批准。虽然非对照系列研究显示出希望，但设计严谨的临床试验寥寥无几，且多数为阴性结果。在缺乏有力试验数据的情况下，移植学会专家共识建议根据临床表型选择证据等级较低的潜在治疗方案。本文重新评估了当前AMR治疗决策的证据基础。我们的结论是：糖皮质激素、利妥昔单抗、硼替佐米及白细胞介素-6(IL-6)拮抗剂缺乏充分证据支持用于AMR治疗。对于早期AMR，可考虑采用免疫吸附技术进行抗体清除，作为血浆置换的替代方案。高剂量静脉注射免疫球蛋白(IVIG)可作为补充治疗，但支持性证据仍有限。虽然以往的临床试验主要针对AMR的病因，但近期关于CD38抗体成功逆转AMR活性的数据(特别是近期II期试验结果)表明，针对抗体与内皮细胞结合所产生的细胞炎症进行干预可能是一种合理策略。基于此思路，在重症早期AMR中，抑制补体系统也可能成为治疗选项。正在进行的II期临床试验评估了长疗程高剂量IVIG、新生儿Fc受体拮抗剂艾加莫德(Efgartigimod)、酪氨酸激酶抑制剂福坦替尼(Fostamatinib)以及补体抑制剂BIVV020；同时，抗IL-6受体抗体托珠单抗(Tocilizumab)和CD38抗体菲泽妥单抗(Felzartamab)的III期试验，为针对AMR病理生物学(Pathobiology)不同环节开发有效且获批的治疗方案带来了希望。 关键词：抗体介导的排斥反应，单采术，CD38，供体特异性抗体，NK细胞 主题：表型、静脉注射免疫球蛋白、炎症、单采术、补体系统蛋白、自然杀伤细胞、血浆置换、糖皮质激素、组织移植、治疗性免疫抑制、抗体、移植、利妥昔单抗、硼替佐米、CD38、抗体介导的排斥反应、托珠单抗、共识、供体、福坦替尼 核心要点： 　•抗体介导排斥反应仍是移植物功能障碍和丢失的主要原因。尽管对该病理机制的认识日益深入，但目前仍缺乏确凿证据支持或获监管机构批准的标准疗法。迄今多项系统性试验均未能证实针对AMR病理生理机制的多种治疗方案(包括利妥昔单抗、硼替佐米及抗IL-6抗体克拉扎珠单抗[Clazakizumab])具有确凿疗效。当前AMR治疗建议主要基于专家意见及来自病例系列、非对照研究和少量系统性试验的有限证据。 　•基于移植学会工作组2019年专家共识，我们推荐单采术(血浆置换或免疫吸附)作为早期AMR(主要由预存供体特异性抗体[DSA]引发)的主要治疗手段。单采术治疗结束后可酌情追加高剂量IVIG治疗。此外，我们强调优化免疫抑制治疗是关键干预措施，尽管一旦抗体已经形成，它不太可能显著影响抗体水平。 　•基于近期有前景的研究数据，我们建议考虑针对抗体介导排斥反应下游病理机制的治疗策略，例如使用CD38抗体疗法干预自然杀伤(NK)细胞引发的移植物损伤。此外，对重症早期AMR患者，依库珠单抗(Eculizumab)抑制补体可能成为潜在治疗选项。 　•在考虑强化免疫抑制措施时，应根据受者年龄和合并症评估排斥反应的活动度与严重程度，同时结合活检显示的不可逆慢性损伤程度(该指标是移植存活期缩短的关键预测因子)来指导治疗强度。 　•建议尽可能将患者纳入前瞻性干预试验，系统性收集改善AMR治疗的证据。目前多项试验正在进行中，包括评估CD38抗体菲泽妥单抗(Felzartamab)和抗白细胞介素-6受体抗体托珠单抗(Tocilizumab)的III期试验，这些药物可对抗B细胞同种免疫反应和炎症。此外，II期临床试验正在探索高剂量IVIG的长期疗程、酪氨酸激酶抑制剂福坦替尼(Fostamatinib)以及Fc受体N亚单位(FcRn)拮抗剂艾加莫德(Efgartigimod)的应用。 引言 　肾移植排斥反应传统上分为两种形式：T细胞介导的排斥反应(TCMR)和抗体介导的排斥反应(AMR)[1,2]。AMR主要由抗供体特异性HLA抗体(DSA)引起，仍是导致移植物失功的主要原因，目前尚无获批的治疗方案且管理指南有限[3]。根据Banff分类标准，AMR的诊断需基于DSA和/或毛细血管C4d沉积检测，远期病例还需结合微血管炎症(MVI)及肾小球或肾小管周围毛细血管的慢性损伤[4]。形态学上，AMR可分为活动型、慢性活动型或慢性(非活动)型等亚型[4]。早期AMR常由预存DSA引发，可导致急性移植物功能障碍；而新生DSA驱动的排斥反应则可能缓慢进展数年。一项涵盖28项研究的系统综述显示，AMR发生率介于3%～12%，其中慢性AMR在10年内累积影响率达7.5%～20.1%[5]。回顾性分析证实AMR是移植物功能衰竭的主要原因，常与药物依从性差相关[6,7]。一项涉及3,131名受者的美国队列研究发现，194例AMR患者即使接受治疗，其死亡删失的移植物失功风险仍高出10倍，且远期AMR风险更为显著[8]。一项针对5,679名AMR患者的研究凸显了AMR带来的重大社会经济与健康影响：患者在两年内出现移植物失功和死亡的风险几乎增加三倍，医疗费用则高出四倍(AMR确诊后两年内，每位患者年均费用达35,750美元)[9]。 　本文基于现有文献探讨了AMR治疗面临的挑战与可选方案，并在此背景下提出我们的建议与意见。 治疗标准 总体考量 缺乏高质量证据 　AMR明确的病理生理学过程提示存在多种潜在的治疗靶点和策略(图1)。然而目前尚无获批的疗法，仅少数治疗方案进入有效性试验阶段，且均未通过III期试验。前瞻性干预试验现状见表1。部分疗法在非对照研究中显示出潜力，但硼替佐米(Bortezomib)[10]、利妥昔单抗(Rituximab)联合或不联合静脉注射免疫球蛋白(IVIG)[11-13]、克拉扎珠单抗(Clazakizumab)[14]及伊米替尼(Imlifidase)[15]的系统性评估均未取得突破性进展，临床应用证据仍显不足。大型III期克拉扎珠单抗试验(IMAGINE；ClinicalTrials.gov标识符NCT03744910)因疗效不足而终止。补体抑制剂(如C1酯酶抑制剂、C1s抗体苏替莫单抗[Sutimlimab]或靶向C5的抗体)的试验同样缺乏令人信服的疗效，包括针对C4d阳性AMR的依库珠单抗(Eculizumab)试验(NCT01895127)亦提前终止[16-18]。但病例系列研究提示其在早期AMR中可能有效[19]。并非所有AMR病例都必然由补体介导，这主要取决于结合内皮细胞的抗体数量(抗体滴度)。事实上，AMR可在无补体活化的情况下发生，因此抑制补体至多只能提供部分解决方案。此前曾将脾切除术作为重症早期AMR的终极治疗手段[20]。我们认为该手术存在长期风险，尤其对年轻患者而言，需进行严格评估；因此，我们的治疗建议中不包含脾切除术。 图1：导致AMR和MVI的病理生理学过程。 B细胞激活并分化为产生抗体的浆细胞后，会产生DSA。DSA结合至微血管内皮细胞，通过补体激活、直接作用或Fcγ受体依赖性效应细胞活化，导致MVI的组织学标志性病变。NK细胞可能通过Fcγ受体IIIA激活，或独立于DSA通过“缺失自我”识别或特定激活受体激活。图示展示了针对B细胞、浆细胞、补体、DSA水平及/或NK细胞的潜在治疗方案。 使用https://BioRender.com绘制。 Ab：抗体；IL-6R：白细胞介素-6受体；C1-INH：C1酯酶抑制剂。 表1：AMR的系统性干预试验 靶点 治疗方法 作用模式 试验阶段 试验缩写 标识符a 第一作者，年份 主要试验结果  DSA 伊米替尼 IgG裂解 II期 (已完成) NCT03897205 Halleck, 2024[15] DSA水平显著短暂降低。对AMR形态学和移植物存活无影响。 血浆置换 Ig清除 Soullilou, 1983[48] 对移植物存活无影响。 Allen, 1993[49] 对移植物存活无影响。 Bonomini, 1985[50] 对移植物存活有显著影响。 免疫吸附 IgG清除 II期(提前终止) AKARIS Böhmig, 2007[51] 治疗组移植物失功较少。 艾加莫德 IgG降低 II期 (招募中) SHAMROCK NCT06503731 尚未完成。  补体 BIVV009 C1s抑制 I期 (已完成) NCT02502903 Eskandary, 2018[18] 对AMR活动度无影响。 BIVV020 II期 (招募中) NCT05156710 尚未完成。 依库珠单抗 靶向C5 III期 (已完成) NCT01327573 Kulkarni, 2017[17] 对活检结果无影响。 II期 (提前终止) NCT01895127 未发表。 C1-INH 靶向补体 II期 (已完成) NCT01147302 Montgomery, 2016[16] 显示肾功能改善趋势。6个月活检中cg较少。 III期 (提前终止) NCT02547220 未发表。 II期 (提前终止) NCT03221842 未发表。  B细胞 利妥昔单抗 B细胞耗竭 III期 (已完成) RITUX-ERAH NCT01066689 Sautenet, 2016[11] 对移植物丢失或肾功能无影响。 II期 (提前终止) TRITON 2010-023746-67 Moreso, 2018[12] 对活检结果和eGFR无影响。 IV期 (提前终止) RituxiCAN-C4 NCT00476164 Shiu, 2020[13] 对临床结局无影响。 III期 (招募中) TAR:GET-1 NCT03994783 尚未完成。 福坦替尼 抑制SYK II期   招募中) FOSTAMR NCT03991780 尚未完成。  先天/适应性免疫 IVIG联合类固醇 多重靶点 II期 (已完成) ACTRN12612000252819 未发表。  IL-6/IL-6R 克拉扎珠单抗 中和IL-6 II期 (已完成) NCT03444103 Doberer, 2021[14] DSA降低；对分子AMR有适度效果(12个月)；可能对eGFR斜率有影响。 II期   已完成) Jordan, 2022[82] eGFR趋于稳定；DSA/移植物炎症减少(非对照试验)。 III期 提前终止) IMAGINE NCT03744910 对eGFR下降无影响。 托珠单抗 阻断IL-6R II期 (招募中) INTERCEPT NCT04561986 尚未完成。  浆细胞 硼替佐米 抑制蛋白酶体 II期   已完成) BORTEJECT NCT01873157 Eskandary, 2018[10] 对DSA水平、形态学/分子活检结果和eGFR斜率无影响。 II期 (已完成) TRIBUTE NCT02201576 已完成，但尚未发表。 II期 (招募中) NCT03737136 尚未完成。  浆细胞/NK细胞 菲泽妥单抗 CD38结合 II期 (已完成) NCT05021484 Mayer, 2024[37] 对AMR活动度有显著影响；NK细胞耗竭；dd-cfDNA显著降低。 菲泽妥单抗 III期 (进行中) TRANSCEND NCT06685757 尚未完成。 cg，移植性肾小球病；C，补体；C1-INH，C1酯酶抑制剂；IL-6R，白细胞介素-6受体；PC，浆细胞；SYK，脾酪氨酸激酶。 a提供的是ClinicalTrials.gov、EudraCT或ANZCTR标识符。 　缺乏有力证据导致临床实践存在显著异质性。2023年欧洲一项在线调查[21]显示，超过半数的慢性活动性AMR患者仅接受优化免疫抑制治疗，未接受任何额外治疗。尽管已知慢性活动性AMR与移植物预后不良相关，但调查中提及的常见不治疗原因包括：认为疾病不可逆转、担忧费用及副作用，以及缺乏可靠的临床试验数据。当采用额外治疗时，静脉注射免疫球蛋白、糖皮质激素冲击疗法和单采术较为常见，而利妥昔单抗或其他生物制剂的使用频率较低[21]。 预防措施 　在缺乏获得批准的治疗手段的情况下，预防AMR至关重要。首要措施包括：实施规范供体配型、优化表位匹配、识别不可接受的HLA抗体以规避有害的预存DSA[22]，并最大限度降低包括新生DSA形成在内的免疫风险[23]。充分的免疫抑制治疗不可或缺[24]，而患者依从性差仍是主要风险因素[6]。服药依从性被视为移植受者的第五大生命体征[25]，需长期获得医生的支持。每日一次的药物方案[26]以及包括移动应用程序或视频咨询在内的“电子”健康解决方案[27]，可改善自我管理和用药依从性。 　定期进行新生DSA筛查可实现早期干预。欧洲器官移植学会工作组指出，该方法能优化无移植物功能障碍患者的长期移植物存活率，尤其是在有效的AMR治疗手段问世的情况下[28]。但争议依然存在。OUTSMART试验将2,000余名参与者随机分为两组：一组根据抗体检测结果接受血清学指导治疗，另一组接受盲法标准治疗[29]。该治疗方案包含患者访谈以促进药物依从性，并优化他克莫司为基础的免疫抑制治疗，但未改变移植物丢失率。虽然该方案降低了活检证实的排斥风险(HR：0.50，P=0.03)，却对其他多种次要结局指标(如患者生存率、移植物功能障碍程度或用药依从性)未产生影响[29]。如本文后面所述，除DSA检测外，其他无创监测工具如供体来源的游离DNA(dd-cfDNA)和尿液趋化因子，目前正作为AMR早期无创监测手段进行评估[30,31]。这些内容将在后续章节详细讨论。 　针对已致敏患者的脱敏方案需进行详细讨论，其中可能包括采用免疫球蛋白G(IgG)裂解酶伊米替尼[32]等技术实现抗体耗竭，但此内容超出本文讨论范围。然而，我们需强调一项队列研究提示：预防性使用依库珠单抗可有效预防早期AMR，尽管长期随访及随机试验未能显示显著获益[33,34]。根据近期病例报告，通过NK细胞耗竭实现脱敏治疗的抗CD38疗法在预防AMR方面展现出潜力，但该策略的推荐仍需长期数据验证[35]。 专家共识 　数年前，在移植学会(TTS)框架下发布了基于专家共识的AMR治疗临床实践指南[3]，其要点见表2。证据等级介于2B至3C(KDIGO编码)，表明专家建议的力度明显不足。该指南强调仅凭组织学无法充分理解AMR的病理生理机制。近期证据支持这一观点：与AMR无法区分的微血管病变可独立于同种异体抗体触发，这可能具有治疗意义[36](另见下文关于抗体独立性NK细胞活化的讨论)。因此需结合额外临床信息(预存DSA与新生DSA；早期AMR与远期AMR)综合评估。对于早期(<30天)或远期(>30天)伴预存DSA的活动性AMR，建议采用血浆置换联合IVIG作为标准治疗方案(SOC)。在存在移植物丢失高风险或合并TCMR反应的重症病例中，建议使用糖皮质激素。建议辅助治疗包括：对早期AMR患者使用补体抑制剂和脾切除术，以及IVIG。此外，还建议优化基础免疫抑制方案：在无糖皮质激素方案中添加糖皮质激素，维持他克莫司血药浓度>5ng/mL，并评估和管理患者依从性问题[3](表2)。 表2：基于专家意见的TTS 2019共识与作者提出的治疗方案(未分级的实践建议) 2019年共识 DSA Banff    2017 表型 标准治疗 考虑辅助治疗  早期急性(<30天) 预存DSA(或非免疫学初次接触) 活动性AMR • PP/IVIGa• 类固醇 • 补体抑制剂• 利妥昔单抗• 脾切除术  远期(>30天) 预存DSA 活动性AMR • PP/IVIGa• 类固醇 • 利妥昔单抗 慢性AMR • 优化基线免疫抑制b 新生DSA 活动性AMR • 优化基线免疫抑制b• 依从性差的评估和管理 • 血浆置换，IVIG• 利妥昔单抗 慢性AMR • IVIG 作者建议 DSA Banff    2022 表型 主要治疗 考虑辅助治疗 在决定治疗类型和强度时考虑以下因素：   • 移植物功能障碍的严重程度和急迫性(例如活动度指数)：可能决定所选治疗的强度。   • 活检时的慢性损伤水平(慢性化指数)：这有助于排除不可改变的慢性损伤。   • 存在合并症：避免与过度免疫抑制相关的风险增加。   • 受者年龄：推测老年患者获益较少。   • 如果诊断出伴有TCMR，还应考虑使用皮质类固醇、ATG或阿仑单抗治疗。   • 考虑进行随访活检以早期发现表型转变(例如，从“疑似AMR”诊断后转变为活动性AMR)或用于治疗监测。  早期(<6个月) 预存(和/或新生)DSA 活动性AMR(慢性活动性AMR) • 单采术(血浆置换或免疫吸附)，联合或不联合IVIGc• 优化基线免疫抑制b • CD38抗体d• 补体抑制e 疑似AMR • 优化基线免疫抑制b • CD38抗体d DSA阴性 MVI, C4d-/DSA阴性 • 优化基线免疫抑制b • CD38抗体d  远期(>6个月) 新生(和/或预存)DSA 活动性/慢性活动性AMR • 优化基线免疫抑制b• CD38抗体d 慢性AMR • 优化基线免疫抑制b 疑似AMR • 优化基线免疫抑制b • CD38抗体d DSA阴性 MVI, C4d-/DSA阴性 • 优化基线免疫抑制b,f • CD38抗体d ATG，抗胸腺细胞球蛋白；PP，血浆置换。 a根据DSA滴度进行每日或隔日血浆置换×6次；每次血浆置换后静脉注射免疫球蛋白100mg/kg，或在血浆置换治疗结束时静脉注射免疫球蛋白2mg/kg b包括使用他克莫司(目标血药浓度>5ng/ml)及维持性糖皮质激素(相当于泼尼松5mg/day)。 c建议进行为期2～3周的血浆置换疗程，初期每日治疗3次，随后改为每2～3日治疗1次。血浆置换疗程结束时可选择性给予高剂量IVIG(2g/kg)。 dCD38靶向治疗可采用达雷妥尤单抗16mg/kg剂量，首月每周给药(前两次给药需预处理以防初次用药反应)，随后每月给药持续至第3-6个月。治疗周期可依据dd-cfDNA监测及/或随访活检结果调整。 e补体抑制可采用依库珠单抗单次或多次给药。 f对于DSA和C4d阴性的微血管病变，可考虑将霉酚酸酯替换为mTOR抑制剂以优化维持性免疫抑制疗法。 CD38靶向治疗作为新选择的出现 　针对CD38(一种在浆细胞和NK细胞表面高表达的分子)的单克隆抗体在AMR治疗中展现出潜力，达雷妥尤单抗(Daratumumab)在病例系列研究中取得积极结果，而菲泽妥单抗(Felzartamab)在远期DSA阳性AMR的随机II期试验中也获得良好数据[37,38]。在该II期试验中，82%的治疗组患者于第24周实现AMR形态学缓解，而安慰剂组仅为20%，且AMR相关转录本及dd-cfDNA水平均显著下降。菲泽妥单抗可大幅降低NK细胞数量，表明其通过耗竭效应细胞(而非直接作用浆细胞)减轻DSA介导的损伤。近期对试验活检样本基因表达模式的重新分析表明，菲泽妥单抗不仅能选择性(且暂时性)影响与AMR活性相关的转录本，更在12个月研究期间持续调节分子损伤与修复反应[39]。输注相关不良反应常见，但未发生严重感染。综上，该试验证实CD38靶向治疗作为安全有效的AMR疗法具有潜力，强调了NK细胞在AMR中的作用，并支持dd-cfDNA作为非侵入性损伤监测工具[37]。 作者2025年实践建议 　鉴于高质量证据的匮乏，我们提出一套基于2019年专家共识(表2、图2)的AMR实用治疗流程。鉴于现有治疗方案的证据基础有限，我们鼓励在条件允许时将患者纳入评估创新治疗方案的干预性试验。我们建议，正如2019年共识所考虑的那样，将AMR的诊断时机(可能仅反映各种混杂因素的不同贡献，如缺血/再灌注损伤的存在、既往免疫反应与初次体液反应、慢性损伤程度等，详见下文)视为特定治疗策略(如DSA清除和补体抑制)有效性的关键决定因素。早期病例常表现为临床显性且形态学上呈活动性AMR，可能多与缺血/再灌注导致的激活移植物内皮上预存DSA相关。相反，远期病例常呈亚临床状态，诊断时表现为慢性损伤(如慢性活动性表型)，通常源于新生DSA。新生DSA在循环系统中的出现可能更为渐进，使内皮有时间适应[40]。为区分早期与远期AMR，并考虑病理生理学、临床表现及形态学呈现的潜在差异，我们提出以6个月为任意阈值——该标准主要源于其在已发表随机对照介入试验中作为“远期”AMR关键入组标准的应用[10,37,38]。然而鉴于该方法的局限性，我们承认这并非严格建议，仅作为一个参考点可在具体病例中灵活应用。例如需注意：早期排斥反应可能源于新生DSA，而远期排斥反应则可能由预存DSA持续存在引发。本实践建议的核心要素包括：进行审慎的风险-获益评估，继而考虑针对DSA的病因治疗及抑制下游免疫活化的干预措施(表2、图2)。 图2：建议的AMR及DSA阴性、C4d阴性MVI治疗流程图。 cg，移植肾小球病；ci，间质纤维化；ct，肾小管萎缩；cv，血管纤维性内膜增厚；g，肾小球炎；IA，免疫吸附；PP，血浆置换；ptc，管周毛细血管炎； TMA，血栓性微血管病。 评估风险-获益以指导治疗强度 　在选择治疗方案前，建议除评估疾病活动度、慢性程度及受者因素外，还需综合考虑肾功能进程及蛋白尿趋势，以此指导治疗类型与强度的决策。此原则同样适用于合并TCMR的患者，糖皮质激素冲击或耗竭抗体治疗可能增加过度免疫抑制风险(表2，图2)。 疾病活度 　建议根据移植物功能障碍程度、动力学变化及形态学疾病活动度调整治疗方案。亚临床或低度炎症的AMR(如程序性活检确诊)通常无需采取高度炎症性病变(如指征活检中存在内膜动脉炎或血栓性微血管病)那样的积极治疗。在此背景下，使用活动度指数可能有助于反映排斥反应过程的强度和临床影响，而不依赖于排斥反应的(亚)类别。2022年Banff会议新成立的工作组[41]的首要目标正是验证这些指数并评估其临床价值。 慢性损伤 　我们还建议通过活检评估慢性损伤程度，这是预测移植物存活期缩短的重要指标，反映了基线肾功能储备水平[42]。该评估(结合反映慢性肾小球损伤程度的蛋白尿水平)对于避免对可能存在不可逆严重损伤的病例进行不必要治疗至关重要。但解读活检结果时必须考虑采样误差的可能性。与活动度指数类似，Banff工作组提出的慢性期指数可辅助临床决策并评估治疗的无效性[41]。 　目前临床实践中，除活检结果外尚缺乏经过验证的可靠预测移植物结局的生物标志物。iBox预测评分作为有前景的工具，可综合评估移植物存活率，其中将DSA水平作为非侵入性标志物纳入考量[43]。但此类工具在临床决策指导中的实用性(尤其是在AMR背景下)仍有待确立。 受者年龄与合并症 　在风险-获益分析中，我们建议考虑受者因素，尤其是年龄和合并症(包括感染或恶性疾病)，这些因素会增加强化免疫抑制治疗引发并发症的风险。在大型移植人群中，受者(及供者)年龄被证实会显著增加功能性移植物丢失的风险[44]。因此，对于老年患者，其移植物功能衰竭可能并非主要由AMR引起，若接受老年供者移植物(伴有供者来源的慢性损伤)，强化治疗可能获益有限，却仍需承受强化免疫抑制带来的相关风险[45]。 病因治疗 　针对根本病因的治疗方案通常更受青睐；在抗体介导性排斥反应中，这意味着针对抗体本身进行干预(表2、图2)。 抗体清除 　我们建议将DSA清除作为早期AMR的主要治疗手段，无论DSA是预存还是新生(尽管多数病例与预存DSA相关，即使未检测到预存DSA的病例也可能涉及供体特异性B细胞记忆)。根据2019年TTS专家共识，可通过单采术(血浆置换或免疫吸附)实现抗体清除。推荐血浆置换疗法基于非对照系列研究结果[46,47]，但与早期对照试验(在明确AMR诊断标准确立前开展)产生了相互矛盾的结果[48-50]。免疫吸附疗法的支持依据来自一项针对重症C4d阳性AMR患者的蛋白A(Protein A)抗体耗竭小规模试验，该试验证明了其在逆转排斥反应方面的获益[51]。然而本文作者意识到免疫吸附疗法可能存在可及性限制且应用尚未普及[51]。此外，目前尚无直接比较不同血液净化技术的头对头试验。单采术疗程可安排在前3天每日进行，随后2～3周内每2～3天进行一次。可考虑联合应用IVIG，但其支持证据较弱，尽管一项回顾性研究提示潜在获益[52]。基于病理生理学考量，我们建议在单采术疗程结束时使用高剂量IVIG(例如2g/kg)，而非每次治疗后使用低剂量的IVIG。近期一项比较IgG裂解酶伊米替尼与血浆置换联合IVIG的试验表明，(短暂)抗体耗竭的概念可能存在局限性[15]。该试验中，已确立为高度致敏移植受者脱敏治疗方案的伊米替尼[32]，在治疗抗体介导排斥反应时，尽管对DSA水平产生显著影响，但未显示优于血浆置换疗法。值得注意的是，尽管辅助使用了糖皮质激素和利妥昔单抗，两种方案均未能在随访活检中显著降低微血管炎症指数。然而由于缺乏未治疗对照组，其对排斥反应活动及进展的真实影响仍不明确[15]。 优化免疫抑制治疗与维持药物依从性 　针对所有抗体相关排斥反应表型，我们建议遵循2019年TTS专家共识，实施优化免疫抑制治疗(同时维持药物依从性)。该建议得到数据支持：免疫抑制强度降低(无论源于患者依从性差或医生指导的调整)均会增加抗体形成及抗体相关性排斥反应发生风险[53]。在此背景下需特别指出：常规维持性免疫抑制剂调整通常基于药物谷浓度(药代动力学方法)，而理想策略应结合免疫抑制功能评估(药效动力学方法)。在这种情况下，一个有趣的策略可能是监测Torque Teno病毒(TTV)，这是一种无处不在的非致病性病毒，其复制受宿主免疫系统调控。血浆中TTV DNA水平升高与免疫抑制水平增加相关。因此，TTV血症正在被研究作为一种反映净免疫功能的动态且可量化的生物标志物，尤其是在移植受者中[54,55]。然而，标准化阈值及临床解读仍需通过更大规模的前瞻性研究进行充分验证。 靶向下游免疫激活 　尽管针对抗体的病因治疗看似是治疗AMR的合理方案，但此类病因治疗的临床疗效证据极为有限。可考虑采用替代方案治疗AMR，即靶向下游抗体依赖性细胞毒性作用和抗体介导的补体激活(表2、图2)。 CD38靶向抗体 　我们建议在早期AMR中联合单采术加用CD38抗体疗法(例如达雷妥尤单抗的超适应症使用，视供应情况而定)，并在远期AMR中推荐其作为单一疗法配合优化免疫抑制治疗，尤其适用于慢性期评分较低的病例。部分受者可能出现CD38靶向疗效不持久的情况，提示需延长至6个月以上的治疗周期[38]。最佳治疗方案及长期副作用尚不明确，使用CD38抗体时应予以考量。此外，指导治疗的优化策略(可能涉及生物标志物)仍在评估中。 补体抑制 　基于观察性研究结果[20]，我们建议在AMR早期严重(难治性)病例中使用依库珠单抗，此类病例可能包括伴有血栓性微血管病变的情况。 治疗监测 　为指导治疗，建议采用常规肾功能评估之外的监测策略，例如DSA(包括其补体结合能力)[56]，以及在条件允许时进行dd-cfDNA评估，并辅以随访活检[57](表2、图2)。尽管支持特定AMR治疗方案的证据有限，其最佳疗程时长仍存在更大不确定性。例如TTS指南建议对活动性AMR进行4～6次血浆置换，但缺乏支持性证据。血浆置换停止后可预期抗体反弹。类似地，菲泽妥单抗试验表明靶向CD38的疗效可能不持久[38]。监测dd-cfDNA(可采用相对比例或绝对浓度形式，以适应总cfDNA的变异性)可能是评估持续性移植物损伤的有效无创工具，因其与AMR相关基因表达及排斥反应形态学表现显著相关[30,58,59]。在近期一项针对40例DSA阳性患者的试验中，将dd-cfDNA指导活检与临床医生指导活检进行对比，结果显示dd-cfDNA检测可显著提前AMR诊断时间(中位数2.8个月 vs. 14.5个月)[60]。此外，纵向监测显示其对AMR的阳性预测值达77%，阴性预测值达85%[60]。最后，dd-cfDNA作为监测工具可能具有检测CD38靶向治疗效果的潜力[37]。但需进一步研究以明确dd-cfDNA监测的临床价值及成本效益。 　本文暂不详述非侵入性生物标志物评估的广泛应用(如早期排斥诊断、预后预测及治疗监测等临床场景)。提升诊断精度的潜在候选指标包括尿液中C-X-C趋化因子10(CXCL10)的检测。尽管作为未来策略具有潜力，趋化因子监测的临床价值仍存争议且需进一步验证[31,61]。近期发表的多中心EU-TRAIN研究反映了当前的不确定性：包括血清信使RNA和非HLA抗体在内的多种生物标志物，其排斥预测能力未能超越标准监测参数及抗HLA DSA[62]。 最新进展 诊断 　Banff分类会根据排斥反应的病理生物学机制及表型谱的最新研究成果持续更新。在Banff 2022方案中，原有的AMR/MVI大类下新增了两个独立的亚类：“MVI、DSA阴性、C4d阴性”及“疑似AMR”，后者特征为循环DSA阳性但MVI低于阈值[4]。DSA-/C4d-阴性表型与AMR存在分子相似性[63,64]，但病理生理机制可能不同[65]。对这类病例的重新分析表明，部分病例涉及DSA结合，而另一些则源于DSA独立机制[66]。一项涵盖30个中心、超过16,000例肾移植活检的研究发现，AMR导致移植物功能衰竭的风险比(HR)为2.7，而DSA阴性MVI的风险比为2.1[67]。DSA阴性且C4d阴性的MVI病例发展为完全AMR及移植肾小球病变的风险升高。该研究显示，疑似AMR虽与移植物功能衰竭关联不显著(风险比1.7)，但其风险水平介于无排斥反应与完全ABMR之间[67]。近年来，大量研究证实了基于活检的转录组分析在急性肾损伤(AKI)中的附加价值，包括分子显微镜诊断系统(MMDx)[68]以及Banff工作组开发的BHOT平台[63]。尽管Banff方案已纳入经验证的分子分析技术，但该技术尚未广泛普及[69]。转录组学可提供预后信息，如远期AMR病例中，损伤/修复相关转录组与估算肾小球滤过率(eGFR)加速下降显著相关[70]。 病理生理学 　传统观点认为DSA诱发的炎症机制包括补体激活、HLA信号介导的内皮效应及Fc受体依赖性途径[1]。近期研究发现，NK细胞作为关键效应细胞，通过结合内皮细胞的DSA与Fcγ受体IIIA被激活[1]。该观点得到以下证据支持：NK细胞转录本占主导地位[71,72]、形态学上NK细胞聚集[73]，以及NK细胞遗传学与MVI的关联性[74]。除经典AMR外，NK细胞还可能参与其他排斥表型，包括DSA阴性、C4d阴性的MVI表型[63,65,75]。不依赖DSA的NK细胞活化可能涉及激活受体或HLA I类错配与抑制性KIR受体模式的结合[65,76]。NK细胞在所有MVI病因中均发挥作用(即使在缺乏DSA的情况下)的观点具有重要治疗意义：通过靶向这些细胞(例如使用CD38抗体[37,38])，可针对下游非特异性免疫激活而非初始病因进行干预。 DSA-与C4d-的MVI 　管理非AMR表型存在额外挑战，尤其在以下情形：C4d或DSA阳性但无MVI、疑似AMR伴临界值下MVI、或C4d与DSA双阴性的MVI。后者需全面复核免疫学数据以确诊排除AMR，包括检测低水平DSA、共享Eplets片段或潜在非HLA反应性。对于这两种MVI亚表型，均建议密切进行临床及血清学监测，并考虑随访活检以检测是否进展为AMR。若确诊为疑似AMR，治疗应遵循既定AMR方案。反之，对于无C4d沉积且可检测到DSA的MVI病例，应避免采用针对DSA的治疗。但一项初步临床研究显示，通过钙调磷酸酶抑制剂与mTOR双重抑制优化维持性免疫抑制，在减轻MVI及预防移植物丢失方面均展现出良好疗效[65]。鉴于这些病理状态最终汇聚于同一通路(涉及NK细胞激活及后续的MVI)且在小鼠实验模型中已证实耗竭NK细胞能有效抑制“缺失自我”抗原诱导的NK细胞介导排斥反应[65]，探索抗CD38疗法显得合乎逻辑(表2，图2)。 正在研究的新疗法 菲泽妥单抗(Felzartamab) 　基于令人鼓舞的II期临床试验结果，CD38抗体药物菲泽妥单抗已获得美国FDA和欧盟委员会授予的AMR治疗孤儿药资格[37,38]。此外，FDA授予其突破性疗法认定。目前正在开展的II期试验扩展研究，通过dd-cfDNA监测探索个性化治疗方案，并已启动III期试验(TRANSCEND；NCT06685757)，旨在成为首个获批的AMR治疗方案[38]。 托珠单抗(Tocilizumab) 　一项研究显示，抗IL-6受体抗体托珠单抗在36例慢性AMR肾移植患者中能稳定肾功能、调节DSA水平并改善组织学表现，由此引发广泛关注[77]。尽管克拉扎珠单抗的IMAGINE试验遭遇挫折，目前仍有一项针对慢性活动性AMR的托珠单抗III期多中心试验正在进行[78]。 高剂量IVIG 　高剂量IVIG在AMR中的作用尚未进行系统研究。澳大利亚开展的一项随机开放标签试验探讨了长达6个月的IVIG联合糖皮质激素冲击疗法的疗效。试验结果尚未公布(ANZCTR标识符：ACTRN12612000252819)。 艾加莫德(Efgartigimod) 　作为获批治疗重症肌无力的FcRn拮抗剂，艾加莫德通过阻断新生儿Fc受体介导的IgG再循环，可降低IgG水平并可能缓解AMR。目前正在开展针对远期AMR的II期临床试验(SHAMROCK；NCT06503731)。 福坦替尼(Fostamatinib) 　实验数据表明，脾酪氨酸激酶抑制剂福坦替尼可预防致敏大鼠产生DSA抗体[80]。目前正在开展II期临床试验评估其在慢性活动性AMR中的应用(NCT03991780)。 BIVV020 　一项II期试验正在评估BIVV020(下一代抗C1s抗体，可阻断经典补体通路)在标准治疗基础上预防和治疗AMR的效果(NCT05156710)。 未来试验设计 　设计AMR干预性试验具有挑战性，需采用严谨的研究设计才能可靠评估新疗法的安全性和有效性。 目标人群 　过于严格的入选标准可能会降低代表性，使招募复杂化，并可能导致试验延迟或提前终止。另一个挑战是更新的Banff方案中不断演变的AMR定义，这可能影响表型分类、移植物存活预测及结果解读。具体而言，将AMR细分为活动性、慢性活动性和慢性亚类无法充分反映实际疾病阶段。在更广泛的AMR范畴内，活动度和慢性指数或许更能提供有效信息并指导入选标准[41]。与欧洲药品管理局的科学交流促成了更严格的AMR定义，该定义可能更适用于临床试验[81]。 对照组设计 　鉴于远期AMR尚无获批治疗方案，在缓慢进展的远期AMR病例中采用优化基础免疫抑制方案的安慰剂对照组在伦理上具有合理性。然而对于具有高移植物丢失风险的临床显性早期AMR，单纯安慰剂设计可能不足，需纳入标准治疗(如单采术)，并将试验药物作为附加治疗与安慰剂进行对照。 终点评估 　评估移植物存活率等硬性终点需要大规模、长期、多中心试验。IMAGINE试验(NCT03744910)旨在评估克拉扎珠单抗治疗慢性活动性AMR的效果，以移植物存活率为主要终点，计划招募350例患者。为缩减样本量和试验周期，研究者选择eGFR斜率作为潜在早期批准的替代终点。然而对200例患者的中期分析显示无显著差异，导致试验终止。有效策略是设计小型II期试验以优化安全性及替代疗效数据，包括MVI演变、分子特征及无创生物标志物。若结果令人鼓舞，可为III期试验设计提供依据。以菲泽妥单抗II期试验为例，其成果促成了更大规模的III期TRANSCEND试验(NCT06685757)。美国FDA批准将组织学AMR活性作为该试验的6个月终点指标，此举或有助于同类研究缩减样本量并缩短试验周期。 总结 　AMR仍是重大挑战，其与移植物存活率低密切相关，尽管存在多种治疗手段，但均未获批临床应用。在这篇专家意见文章中，建议针对不同MVI表型优化基础免疫抑制方案：单采术或补体抑制剂可保留用于早期AMR，糖皮质激素冲击疗法适用于伴有TCMR的排斥反应。尽管多项评估不同治疗方案的试验结果令人失望，但抗CD38疗法已显现出极具前景的新策略。近期一项探索性II期试验表明，该疗法通过耗竭NK细胞可有效抑制AMR的活动度。该随机试验结果结合个案报告及病例系列的积极发现，促使作者提出将CD38靶向治疗作为不同AMR表型的辅助疗法，甚至可用于无C4d沉积或DSA的MVI病例。但移植领域长期安全性数据尚缺，需待正在进行的III期试验结果。目前多项创新策略正在探索中，为更好的管理带来了希望。 (搬运工：中庸) 作者信息 1.维也纳医科大学医学三院肾病与透析科，奥地利，维也纳 2.鲁汶大学微生物学、免疫学与移植学系，比利时，鲁汶  3.布拉格临床与实验医学研究所肾内科，捷克，布拉格 4.格勒诺布尔阿尔卑斯大学中心医院肾病、血液净化与移植科，法国，格勒诺布尔 5.巴塞尔大学附属医院移植免疫与肾病诊所，瑞士，巴塞尔  6.里昂市立爱德华·赫里奥医院移植、肾病与临床免疫学系，法国，里昂 7.夏里特大学医学中心肾内科，德国，柏林 来源 Nephrology Dialysis Transplantation, Volume 40, Issue 8, August 2025, Pages 1615–1627 DOI: 10.1093/ndt/gfaf097 © The Author(s) 2025. 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