Sperinde Gizette, Webb-Vargas Yenny, Hu Zicheng, Saha Ashis, Hammer Christian, Erickson Richard, Eden Chris, Galloway Deanna, Jacob-Moffatt Rhian, Siradze Ketevan, Nguyen Van, Fischer Saloumeh K
BioAnalytical Sciences, Genentech, Inc. 1 DNA Way, South San Francisco, CA, United States of America.
Biostats Non-Clinical PT, Genentech, Inc. 1 DNA Way, South San Francisco, CA, United States of America.
AAPS J. 2025 Jun 6;27(4):107. doi: 10.1208/s12248-025-01090-1.
Ulcerative colitis (UC) and Crohn's disease (CD), pose a substantial burden, necessitating effective therapies. Etrolizumab, a unique monoclonal antibody targeting integrins, initially showed promise but was terminated due to lack of efficacy in PhIII studies. The immune responses elicited by patients towards etrolizumab make it a compelling subject for further in-depth investigation. This study delves into immunogenic responses to etrolizumab, examining factors contributing to such responses, including anti-drug antibody (ADA) assay format, patient baseline characteristics, immunosuppressive (IS) medication use, human leukocyte antigen (HLA) allelic expression, and the clinical impact of ADA responses on safety and efficacy endpoints. Logistic regression was used to test for association between the presence of ADA & (neutralizing antibody) NAb and HLA alleles with carrier frequencies of at least 2%, alongside age, sex, and IS use. We identified two class-II HLA alleles, HLA-DQB106:03 and HLADQA1 03:03, associated with the development of ADA and NAb. However, there was minimal impact of ADA on clinical parameters, such as pharmacokinetics (PK), safety, and efficacy. The findings enhance our understanding of etrolizumab immunogenicity, in the context of clinical impact, providing insights that may inform future biologic development strategies and patient selection criteria in IBD clinical trials.
溃疡性结肠炎（UC）和克罗恩病（CD）带来了沉重负担，因此需要有效的治疗方法。艾托珠单抗是一种靶向整合素的独特单克隆抗体，最初显示出一定前景，但因在III期研究中缺乏疗效而终止。患者对艾托珠单抗产生的免疫反应使其成为进一步深入研究的引人关注的对象。本研究深入探讨了对艾托珠单抗的免疫原性反应，研究了导致此类反应的因素，包括抗药物抗体（ADA）检测方法、患者基线特征、免疫抑制（IS）药物使用、人类白细胞抗原（HLA）等位基因表达，以及ADA反应对安全性和疗效终点的临床影响。采用逻辑回归分析来检验ADA和（中和抗体）NAb的存在与携带频率至少为2%的HLA等位基因之间，以及与年龄、性别和IS使用之间的关联。我们鉴定出两个II类HLA等位基因，即HLA-DQB106:03和HLA-DQA103:03，它们与ADA和NAb的产生相关。然而，ADA对临床参数（如药代动力学（PK）、安全性和疗效）的影响极小。这些发现增进了我们在临床影响背景下对艾托珠单抗免疫原性的理解，为未来炎症性肠病（IBD）临床试验中的生物制剂开发策略和患者选择标准提供了参考依据。
