Development of antidrug antibodies against adalimumab maps to variation within the HLA-DR peptide-binding groove.
Development of antidrug antibodies against adalimumab maps to variation within the HLA-DR peptide-binding groove.
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DOI：
10.1172/jci.insight.156643
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发表时间：
2023-02-22
期刊：
影响因子：
8
通讯作者：
Simpson, Michael A.
中科院分区：
文献类型：
--
作者：
Tsakok, Teresa;Saklatvala, Jake;Rispens, Theo;Loeff, Floris C.;de Vries, Annick;Allen, Michael H.;Barbosa, Ines A.;Baudry, David;Dasandi, Tejus;Duckworth, Michael;Meynell, Freya;Russell, Alice;Chapman, Anna;McBride, Sandy;McKenna, Kevin;Perera, Gayathri;Ramsay, Helen;Ramesh, Raakhee;Sands, Kathleen;Shipman, Alexa;Burden, A. David;Griffiths, Christopher E. M.;Reynolds, Nick J.;Warren, Richard B.;Mahil, Satveer;Barker, Jonathan;Dand, Nick;Smith, Catherine;Simpson, Michael A.
靶向生物治疗可引起以抗药物抗体（ADA）发展为特征的不良宿主免疫反应，这是治疗失败的重要原因。最广泛使用的生物免疫介导疾病是阿达木单抗，一种肿瘤坏死因子抑制剂。本研究旨在确定导致抗阿达木单抗ADA发展的遗传变异，从而影响治疗失败。在首次接受阿达木单抗治疗的银屑病患者中，在开始治疗后6-36个月评估血清ADA，我们观察到在主要组织相容性复合体（MHC）中ADA与阿达木单抗的全基因组关联。结合信号映射到HLA-DR肽结合槽的第9位色氨酸和第71位赖氨酸的存在，这两个残基都具有抗ADA的保护作用。强调其临床相关性，这些残留物也对治疗失败有保护作用。我们的研究结果强调了抗原肽通过MHC II类呈递是ADA对抗生物疗法和下游治疗反应发展的关键机制。
Targeted biologic therapies can elicit an undesirable host immune response characterized by the development of antidrug antibodies (ADA), an important cause of treatment failure. The most widely used biologic across immune-mediated diseases is adalimumab, a tumor necrosis factor inhibitor. This study aimed to identify genetic variants that contribute to the development of ADA against adalimumab, thereby influencing treatment failure. In patients with psoriasis on their first course of adalimumab, in whom serum ADA had been evaluated 6–36 months after starting treatment, we observed a genome-wide association with ADA against adalimumab within the major histocompatibility complex (MHC). The association signal mapped to the presence of tryptophan at position 9 and lysine at position 71 of the HLA-DR peptide-binding groove, with both residues conferring protection against ADA. Underscoring their clinical relevance, these residues were also protective against treatment failure. Our findings highlight antigenic peptide presentation via MHC class II as a critical mechanism in the development of ADA against biologic therapies and downstream treatment response.
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影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian
影响因子：
8.6
作者：
Barbosa, MDFS;Vielmetter, J;Jacinto, J
通讯作者：
Jacinto, J
影响因子：
3.7
作者：
Liu M;Degner J;Davis JW;Idler KB;Nader A;Mostafa NM;Waring JF
通讯作者：
Waring JF
DOI：
10.1165/ajrcmb.25.3.4261
发表时间：
2001-09-01
影响因子：
6.4
作者：
Foley, PJ;McGrath, DS;du Bois, RM
通讯作者：
du Bois, RM
影响因子：
9.8
作者：
Nair, RP;Stuart, PE;Elder, JT
通讯作者：
Elder, JT