Reppell Mark, Zheng Xiuwen, Dreher Ingeborg, Blaes Jonas, Regan Elina, Haslberger Tobias, Guay Heath, Pivorunas Valerie, Smaoui Nizar
AbbVie Inc., North Chicago, IL, USA.
AbbVie Deutschland GmbH & Co, KG, Ludwigshafen, Germany.
J Crohns Colitis. 2025 Jan 11;19(1). doi: 10.1093/ecco-jcc/jjae129.
Anti-tumor necrosis factor (anti-TNF) therapies are commonly prescribed treatments for Crohn's disease (CD) and ulcerative colitis (UC). Many patients treated with anti-TNF therapy eventually develop anti-drug antibodies (ADAs). Understanding the factors associated with immunogenicity in anti-TNF-treated patients can help guide treatment. The Humira SERENE studies were Phase 3 trials investigating adalimumab induction regimens in CD and UC patients.
We imputed alleles for 7 HLA genes in 1100 patients from the SERENE CD and SERENE UC trials. We then tested these alleles for association with time to immunogenicity. Subsequently, we tested loci significantly associated with immunogenicity for their association with patients who had consistently low drug serum concentrations.
This study replicated the association of HLA-DQA105 with time to immunogenicity (hazard ratio [HR] 1.42, p = 2.22E-06). Specifically, HLA-DQA105:05 was strongly associated (HR 1.76, p = 2.02E-10) and we detected a novel association represented by HLA-DRB101:02 (HR 3.16, p = 2.92E-07). Carriage of HLA-DQA105:05 and HLA-DRB101:02 was associated with patients who experienced consistently low adalimumab trough concentrations (HLA-DQA105:05: odds ratio [OR] 1.98, p = 0.0049; HLA DRB1*01:02: OR 7.06, p = 7.44E-05).
We found a significant association between alleles at genes in the human HLA locus and the formation of adalimumab immunogenicity and low adalimumab drug serum concentrations in large clinical studies of CD and UC patients. This work extends previous findings in CD to UC and directly shows a genetic association in patients with low drug concentrations. This work builds on existing literature to suggest that genetic screening could be a useful tool for clinicians concerned with patient anti-TNF immunogenicity.
SERENE CD (NCT02065570), SERENE UC (NCT02065622).
抗肿瘤坏死因子（抗TNF）疗法是克罗恩病（CD）和溃疡性结肠炎（UC）常用的治疗方法。许多接受抗TNF治疗的患者最终会产生抗药抗体（ADA）。了解抗TNF治疗患者免疫原性相关因素有助于指导治疗。Humira SERENE研究是调查阿达木单抗在CD和UC患者中诱导方案的3期试验。
我们对来自SERENE CD和SERENE UC试验的1100名患者的7个HLA基因的等位基因进行了推算。然后我们测试这些等位基因与免疫原性发生时间的关联。随后，我们测试与免疫原性显著相关的基因座与药物血清浓度持续较低的患者之间的关联。
本研究重复了HLA - DQA105与免疫原性发生时间的关联（风险比[HR] 1.42，p = 2.22E - 06）。具体而言，HLA - DQA105:05有强烈关联（HR 1.76，p = 2.02E - 10），并且我们检测到由HLA - DRB101:02代表的新关联（HR 3.16，p = 2.92E - 07）。携带HLA - DQA105:05和HLA - DRB101:02与阿达木单抗谷浓度持续较低的患者相关（HLA - DQA105:05：优势比[OR] 1.98，p = 0.0049；HLA DRB1*01:02：OR 7.06，p = 7.44E - 05）。
在CD和UC患者的大型临床研究中，我们发现人类HLA基因座中的等位基因与阿达木单抗免疫原性的形成以及阿达木单抗药物血清浓度低之间存在显著关联。这项工作将先前在CD中的发现扩展到UC，并直接显示了药物浓度低的患者中的基因关联。这项工作以现有文献为基础，表明基因筛查可能是关注患者抗TNF免疫原性的临床医生的有用工具。
SERENE CD（NCT02065570），SERENE UC（NCT02065622）。
