Immunogenicity of biomolecules is one of the largest concerns in biological therapeutic drug development. Adverse immune responses as a result of immunogenicity to biotherapeutics range from mild hypersensitivity reactions to potentially life-threatening anaphylactic reactions and can negatively impact human health and drug efficacy. Numerous confounding patient-, product- or treatment-related factors can influence the development of an immune reaction against therapeutic proteins. The goal of this study was to investigate the relationship between pre-existing drug reactivity (PE-ADA), individual immunogenetics (MHC class II haplotypes), and development of treatment-induced antidrug antibodies (TE-ADA) in cynomolgus macaque. PE-ADA refers to the presence of antibodies immunoreactive against the biotherapeutic in treatment-naïve individuals. We observed that PE-ADA frequency against four different bispecific antibodies in naïve cynomolgus macaque is similar to that reported in humans. Additionally, we report a trend towards an increased incidence of TE-ADA development in macaques with high PE-ADA levels. In order to explore the relationship between MHC class II alleles and risk of ADA development, we obtained full-length MHC class II sequences from 60 cynomolgus macaques in our colony. We identified a total of 248 DR, DP, and DQ alleles and 236 unique haplotypes in our cohort indicating a genetically complex set of animals potentially reflective of the human population. Based on our observations, we propose the evaluation of the magnitude/frequency of pre-existing reactivity and consideration of MHC class II genetics as additional useful tools to understand the immunogenic potential of biotherapeutics.

中文翻译：

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食蟹猕猴中抗药抗体，已存在的抗药反应性和免疫遗传学（MHC II类等位基因）之间的相关性。

生物分子的免疫原性是生物治疗药物开发中最大的关注之一。对生物治疗剂的免疫原性导致的不良免疫反应范围从轻度的超敏反应到可能危及生命的过敏反应，会对人体健康和药物疗效产生负面影响。许多与患者，产品或治疗相关的混杂因素会影响针对治疗性蛋白质的免疫反应的发展。这项研究的目的是调查食蟹猕猴中既有的药物反应性（PE-ADA），个体免疫遗传学（MHC II类单倍型）与治疗诱导的抗药物抗体（TE-ADA）之间的关系。PE-ADA是指在未接受过治疗的个体中对生物疗法具有免疫反应性的抗体的存在。我们观察到幼稚猕猴中针对四种不同双特异性抗体的PE-ADA频率与人类报道的频率相似。此外，我们报告了高PE-ADA水平的猕猴中TE-ADA发生率增加的趋势。为了探索MHC II类等位基因与ADA发生风险之间的关系，我们从菌落中的60个食蟹猕猴获得了全长MHC II类序列。我们在我们的队列中共鉴定了248个DR，DP和DQ等位基因和236个独特的单倍型，这表明遗传上复杂的动物可能反映了人类的种群。根据我们的观察，