Department of Gastroenterology, Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Ramat-Gan, Israel.
Department of Molecular Microbiology and Biotechnology, Tel-Aviv University, Tel-Aviv, Israel.
Gut. 2016 Jul;65(7):1132-8. doi: 10.1136/gutjnl-2015-309290. Epub 2015 Apr 20.
The cross-immunogenicity of the recently approved infliximab-biosimilar Remsima (CT-P13) with the originator drug Remicade is still unknown.
Sera of patients with IBD with or without measurable anti-Remicade antibodies to infliximab (ATI) were tested for their cross-reactivity to two batches of Remsima. Experiments were repeated after deglycosylation of Remicade/Remsima, IgG purification, excipients' dialysis and monomer purification by size exclusion chromatography. Anti-Remicade antibodies were tested for their functional inhibition of TNF-α binding by Remsima/Remicade by competition assay. Cross-reactivity of anti-adalimumab antibodies with Remicade/Remsima was also investigated.
125 patients' and controls' sera were tested (median age 31 years, IQR 24.5-39.5). All 56 anti-Remicade ATI-negative controls (14 healthy individuals, 42 patients with IBD) were also negative for anti-Remsima ATI. All 69 positive anti-Remicade IBD sera were cross-reactive with Remsima. ATI titres against Remicade or Remsima were strongly correlated (r values between 0.92 and 0.99, p<0.001 for all experiments, Spearman's correlation test). The background ELISA signal for Remsima was slightly higher compared with Remicade in negative controls (1.25±0.6 µg/mL vs 0.76±0.5 µg/mL, respectively, p<0.001), and persisted after deglycosylation, dialysis or protein size filtration, but abolished by IgG purification and significantly diminished by monomer purification. Anti-Remicade ATIs of patients with IBD (n=10) exerted similar functional inhibition on Remsima or Remicade TNF-α binding capacity (p=NS for all inhibition curve points). Antibodies-to-adalimumab in adalimumab-treated patients with IBD (n=7) did not cross-react with either Remicade or Remsima.
Anti-Remicade antibodies in patients with IBD recognise and functionally inhibit Remsima to a similar degree, suggesting similar immunogenicity and shared immunodominant epitopes on these two infliximab agents. In contrast, anti-adalimumab antibodies do not cross-react with Remsima or Remicade.
最近批准的英夫利昔单抗生物类似药 Remsima（CT-P13）与原研药 Remicade 的交叉免疫原性尚不清楚。
本研究检测了伴有或不伴有可测量抗 Remicade 英夫利昔单抗抗体（ATI）的 IBD 患者的血清对两种 Remsima 批次的交叉反应性。在 Deglycosylation 去除 Remicade/Remsima、IgG 纯化、透析赋形剂和通过分子筛色谱法纯化单体后，重复了实验。通过竞争测定法检测抗 Remicade 抗体对 TNF-α结合的功能抑制作用，以检测抗 Remicade 抗体对 Remsima/Remicade 的功能抑制作用。还研究了抗阿达木单抗抗体与 Remicade/Remsima 的交叉反应性。
共检测了 125 例患者和对照者的血清（中位年龄 31 岁，IQR 24.5-39.5）。所有 56 例抗 Remicade ATI 阴性对照者（14 例健康个体，42 例 IBD 患者）也均为抗 Remsima ATI 阴性。所有 69 例阳性抗 Remicade IBD 血清均与 Remsima 发生交叉反应。抗 Remicade 或 Remsima 的 ATI 滴度与 Remicade 或 Remsima 呈强相关（所有实验的 r 值在 0.92 到 0.99 之间，p<0.001，Spearman 相关检验）。阴性对照者中，Remsima 的背景 ELISA 信号略高于 Remicade（分别为 1.25±0.6 µg/mL 和 0.76±0.5 µg/mL，p<0.001），且在去糖基化、透析或蛋白质大小过滤后仍存在，但 IgG 纯化后被消除，单体纯化后显著降低。IBD 患者的抗 Remicade ATI（n=10）对 Remsima 或 Remicade TNF-α结合能力的功能抑制作用相似（所有抑制曲线点的 p=NS）。IBD 接受阿达木单抗治疗的患者的抗体-to-adalimumab（n=7）与 Remicade 或 Remsima 均无交叉反应。
IBD 患者的抗 Remicade 抗体识别并以相似的程度抑制 Remsima，提示这两种英夫利昔单抗药物具有相似的免疫原性和共同的免疫显性表位。相比之下，抗阿达木单抗抗体与 Remsima 或 Remicade 不发生交叉反应。
