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首页> 外文期刊>Clinical and Experimental Immunology: An Official Journal of the British Society for Immunology >Contribution of enhanced engagement of antigen presentation machinery to the clinical immunogenicity of a human interleukin (IL)-21 receptor-blocking therapeutic antibody
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Contribution of enhanced engagement of antigen presentation machinery to the clinical immunogenicity of a human interleukin (IL)-21 receptor-blocking therapeutic antibody

机译：抗原呈递机制参与度的提高对人白介素（IL）-21受体阻断性治疗抗体的临床免疫原性的贡献

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摘要

Reliable risk assessment for biotherapeutics requires accurate evaluation of risk factors associated with immunogenicity. Immunogenicity risk assessment tools were developed and applied to investigate the immunogenicity of a fully human therapeutic monoclonal antibody, ATR-107 [ anti-interleukin (IL)-21 receptor] that elicited anti-drug antibodies (ADA) in 76% of healthy subjects in a Phase 1 study. Because the ATR-107 target is expressed on dendritic cells (DCs), the immunogenicity risk related to engagement with DC and antigen presentation pathways was studied. Despite the presence of IL-21R on DCs, ATR-107 did not bind to the DCs more extensively than the control therapeutic antibody (PF-1) that had elicited low clinical ADA incidence. However, ATR-107, but not the control therapeutic antibody, was translocated to the DC late endosomes, colocalized with intracellular antigen-D related (HLA-DR) molecules and presented a dominant T cell epitope overlapping the complementarity determining region 2 (CDR2) of the light chain. ATR-107 induced increased DC activation exemplified by up-regulation of DC surface expression of CD86, CD274 (PD-L1) and CD40, increased expansion of activated DC populations expressing CD86(hi), CD40(hi), CD83(hi), programmed death ligand 1 (PD-L1)(hi), HLA-DRhi or CCR7(hi), as well as elevated secretion of tumour necrosis factor (TNF)-alpha by DCs. DCs exposed to ATR-107 stimulated an autologous T cell proliferative response in human donor cells, in concert with the detection of immunoglobulin (Ig) G-type anti-ATR-107 antibody response in clinical samples. Collectively, the enhanced engagement of antigen presentation machinery by ATR-107 was suggested. The approaches and findings described in this study may be relevant to identifying lower immunogenicity risk targets and therapeutic molecules.
机译：对生物疗法进行可靠的风险评估需要对与免疫原性相关的风险因素进行准确的评估。开发了免疫原性风险评估工具，并将其用于调查完全人类治疗性单克隆抗体ATR-107 [抗白介素（IL）-21受体]的免疫原性，该抗体在76％的健康受试者体内诱发了抗药物抗体（ADA）。 1期研究。由于ATR-107靶标在树突状细胞（DC）上表达，因此研究了与DC和抗原呈递途径结合的免疫原性风险。尽管DC上存在IL-21R，但ATR-107与DC的结合并不比引起临床ADA发病率低的对照治疗性抗体（PF-1）更广泛。然而，ATR-107而非对照治疗性抗体被转移至DC晚期内体，与细胞内抗原D相关（HLA-DR）分子共定位，并呈现出与互补决定区2（CDR2）重叠的显性T细胞表位。的轻链。 ATR-107诱导的DC活化增强，例如CD86，CD274（PD-L1）和CD40的DC表面表达上调，表达CD86（hi），CD40（hi），CD83（hi）的活化DC群体的扩增增加。程序性死亡配体1（PD-L1）（hi），HLA-DRhi或CCR7（hi），以及DC分泌的肿瘤坏死因子（TNF）-α升高。暴露于ATR-107的DC刺激了人类供体细胞中的自体T细胞增殖反应，与临床样品中免疫球蛋白（Ig）G型抗ATR-107抗体反应的检测相一致。总体上，提出了ATR-107增强抗原呈递机制的参与。这项研究中描述的方法和发现可能与确定较低的免疫原性风险靶标和治疗性分子有关。

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