Zhang Brian C, Schneider-Hohendorf Tilman, Elyanow Rebecca, Pignolet Beatrice, Falk Simon, Wünsch Christian, Deffner Marie, Yusko Erik, May Damon, Mattox Daniel, Dawin Eva, Gerdes Lisa Ann, Bucciarelli Florence, Revie Lisa, Antony Gisela, Jarius Sven, Seidel Christiane, Senel Makbule, Bittner Stefan, Luessi Felix, Havla Joachim, Knop Matthias, Friese Manuel A, Rothacher Susanne, Salmen Anke, Hayashi Fumie, Henry Roland, Caillier Stacy, Santaniello Adam, Seipelt Maria, Heesen Christoph, Nischwitz Sandra, Bayas Antonios, Tumani Hayrettin, Then Bergh Florian, Meyer Zu Hörste Gerd, Kümpfel Tania, Gross Catharina C, Wildemann Brigitte, Kerschensteiner Martin, Gold Ralf, Meuth Sven G, Zipp Frauke, Cree Bruce A C, Oksenberg Jorge, Wilson Michael R, Hauser Stephen L, Zamvil Scott S, Klotz Luisa, Liblau Roland, Robins Harlan, Sabatino Joseph J, Wiendl Heinz, Schwab Nicholas
Adaptive Biotechnologies, Seattle, WA, USA.
Department of Neurology, University of Muenster, Muenster, Germany.
EBioMedicine. 2025 Jul 31;118:105873. doi: 10.1016/j.ebiom.2025.105873.
Glatiramer acetate (GA) is a well-tolerated treatment for multiple sclerosis (MS) and comparable in its efficacy to high-dose interferon beta (IFN). As a lack of validated treatment response biomarkers for MS hampers progress in personalised treatment, the study goal was to search for biomarkers of a successful treatment response utilising the known observation of T-cell expansions after GA treatment.
T-cell receptor beta chain (TRB) sequencing was performed in 3021 patients with MS: a discovery cohort of 1627 patients with MS, 204 of whom had previously been treated with GA, and then validated in 1394 patients with MS, 424 of whom had previously been treated with GA. Clinical data from 1987 patients with MS treated with GA or IFN and available HLA information from the NationMS, ACP, EPIC, BIONAT, and CombiRx trial cohorts were used for a subsequent analysis.
Common GA-associated TRB expansions were exclusively detected in HLA-A∗03:01 or in HLA-DRB1∗15:01 backgrounds, within CD8+ effector- or CD4+ central-memory T cells. Both sets of common sequences clonally expanded after GA treatment in a first validation cohort and predicted GA exposure in two further validation cohorts. To evaluate whether restriction of public TRBs to only two HLA alleles is also associated with GA's clinical efficacy, we analysed five cohorts of patients with MS for a potential benefit of the two HLAs concerning the GA response compared to IFN. We consistently found positive interactions with HLA-A∗03:01. This included a relative reduction in relapse risk compared to IFN in HLA-A∗03:01 carriers of 33% (CombiRx: GA + IFN arm: HR 0.67 [95% CI: 0.47-0.96], p = 0.0269) and 34% (CombiRx: GA arm: HR 0.66 [95% CI: 0.45-0.98], p = 0.0377), and in risk to first relapse of 63% (NationMS: HR 0.37 [95% CI: 0.16-0.88], p = 0.0246), but no positive association with DRB1∗15:01.
HLA-A∗03:01 carrying patients with MS specifically benefit from GA treatment and GA significantly outperforms IFN in these patients. Therefore, determining HLA-A∗03:01 status before choosing a platform treatment for MS, would allow for a personalised treatment decision between GA and IFN.
German Research Foundation, National Institutes of Health, National Multiple Sclerosis Society, Valhalla Foundation, Westridge Foundation, Mayer Foundation, German Federal Ministry of Education and Research.
醋酸格拉替雷（GA）是一种耐受性良好的多发性硬化症（MS）治疗药物，其疗效与高剂量干扰素β（IFN）相当。由于缺乏经过验证的MS治疗反应生物标志物阻碍了个性化治疗的进展，本研究的目标是利用GA治疗后T细胞扩增的已知观察结果来寻找成功治疗反应的生物标志物。
对3021例MS患者进行了T细胞受体β链（TRB）测序：一个由1627例MS患者组成的发现队列，其中204例曾接受过GA治疗，然后在1394例MS患者中进行验证，其中424例曾接受过GA治疗。来自1987例接受GA或IFN治疗的MS患者临床数据以及来自NationMS、ACP、EPIC、BIONAT和CombiRx试验队列的可用HLA信息用于后续分析。
常见的GA相关TRB扩增仅在HLA-A∗03:01或HLA-DRB1∗1:01背景下的CD8+效应T细胞或CD4+中央记忆T细胞中检测到。在第一个验证队列中，两组常见序列在GA治疗后克隆性扩增，并在另外两个验证队列中预测GA暴露情况。为了评估公共TRB仅限制于两个HLA等位基因是否也与GA的临床疗效相关，我们分析了五个MS患者队列，以探讨这两个HLA在GA反应方面相对于IFN的潜在益处。我们始终发现与HLA-A∗03:01存在正向相互作用。这包括与IFN相比，HLA-A∗03:01携带者的复发风险相对降低33%（CombiRx：GA + IFN组：HR 0.67 [95% CI：0.47-0.96]，p = 0.0269）和34%（CombiRx：GA组：HR 0.66 [95% CI：0.45-0.98]，p = 0.0377），首次复发风险降低63%（NationMS：HR 0.37 [95% CI：0.16-0.88]，p = 0.0246），但与DRB1∗15:01无正向关联。
携带HLA-A∗03:01的MS患者特别受益于GA治疗，且GA在这些患者中显著优于IFN。因此，在为MS选择平台治疗之前确定HLA-A∗03:01状态，将有助于在GA和IFN之间做出个性化治疗决策。
德国研究基金会、美国国立卫生研究院、美国国家多发性硬化症协会、瓦尔哈拉基金会、韦斯特里奇基金会、梅耶基金会、德国联邦教育与研究部。
