Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Sci Rep. 2022 Mar 11;12(1):4266. doi: 10.1038/s41598-022-07997-5.
In this largest to-date genetic analysis of anti-drug antibody (ADA) response to a therapeutic monoclonal antibody (MAb), genome-wide association was performed for five measures of ADA status among 8844 individuals randomized to bococizumab, which targets PCSK9 for LDL-C lowering and cardiovascular protection. Index associations prioritized specific amino acid substitutions at the DRB1 and DQB1 MHC class II genes rather than canonical haplotypes. Two clusters of missense variants at DRB1 were associated with general ADA measures (residues 9, 11, 13; and 96, 112, 120, 180) and a third cluster of missense variants in DQB1 was associated with ADA measures including neutralizing antibody (NAb) titers (residues 66, 67, 71, 74, 75). The structural disposition of the missense substitutions implicates peptide antigen binding and CD4 effector function, mechanisms that are potentially generalizable to other therapeutic mAbs.Clinicaltrials.gov: NCT01968954, NCT01968967, NCT01968980, NCT01975376, NCT01975389, NCT02100514.
在这项迄今为止规模最大的针对治疗性单克隆抗体 (MAb) 的抗药物抗体 (ADA) 反应的全基因组关联分析中，对 8844 名接受 bococizumab 治疗的个体的 ADA 状态的五项指标进行了全基因组关联分析，该药物针对 PCSK9 降低 LDL-C 和心血管保护。索引关联优先考虑 DRB1 和 DQB1 MHC Ⅱ类基因中特定氨基酸取代，而不是经典单倍型。DRB1 中有两个错义变异簇与一般 ADA 指标相关（残基 9、11、13；和 96、112、120、180），DQB1 中有第三个错义变异簇与包括中和抗体 (NAb) 滴度在内的 ADA 指标相关（残基 66、67、71、74、75）。错义替换的结构排列暗示了肽抗原结合和 CD4 效应功能，这些机制可能推广到其他治疗性 MAb。Clinicaltrials.gov：NCT01968954、NCT01968967、NCT01968980、NCT01975376、NCT01975389、NCT02100514。
