Clinical Immunology, Medical Sciences, Amgen Inc, One Amgen Center Drive, 30E-3-B, Thousand Oaks, CA, 91320, USA,
Ann Hematol. 2010 Jul;89 Suppl 1(Suppl 1):75-85. doi: 10.1007/s00277-010-0908-2. Epub 2010 Feb 13.
Romiplostim is an Fc-peptide fusion protein that activates intracellular transcriptional pathways via the thrombopoietin (TPO) receptor leading to increased platelet production. Romiplostim has been engineered to have no amino acid sequence homology to endogenous TPO. Recombinant protein therapeutics can be at a risk of development of an antibody response that can impact efficacy and safety. Hence, a strategy to detect potential antibody formation to the drug and to related endogenous molecules can be useful. The immunogenicity assessment strategy involved both the detection and characterization of binding and neutralizing antibodies. The method for detection was based on a surface plasmon resonance biosensor platform using the Biacore 3000. Samples that tested positive for binding antibodies in the Biacore immunoassay were then tested in a neutralization assay. Serum samples from 225 subjects with immune thrombocytopenic purpura (ITP) dosed with romiplostim and 45 ITP subjects dosed with placebo were tested for romiplostim and TPO antibodies. Prior to romiplostim treatment, 17 subjects (7%) tested romiplostim antibody positive and 12 subjects (5%) tested TPO antibody positive for pre-existing binding antibodies. After romiplostim exposure, 11% of the subjects exhibited binding antibodies against romiplostim and 5% of the subjects with ITP showed binding antibodies against TPO. The antibodies against romiplostim did not cross-react with TPO and vice versa. No cases of anti-TPO neutralizing antibodies were detected in romiplostim-treated subjects. The incidence of anti-romiplostim neutralizing antibodies to romiplostim was 0.4% (one subject); this subject tested negative at the time of follow-up 4 months later. No impact on platelet profiles were apparent in subjects that had antibodies to romiplostim to date. In summary, administration of romiplostim in ITP subjects resulted in the development of a binding antibody response against romiplostim and TPO ligand. One subject developed a neutralizing antibody response to romiplostim that impacted the platelet counts of this subject. No neutralizing antibodies to endogenous TPO were observed.
罗米司亭是一种 Fc-肽融合蛋白，通过血小板生成素（TPO）受体激活细胞内转录途径，导致血小板生成增加。罗米司亭经过工程设计，与内源性 TPO 没有氨基酸序列同源性。重组蛋白治疗药物可能存在产生针对药物和相关内源性分子的抗体反应的风险，因此，一种用于检测潜在药物抗体形成和相关内源性分子的策略可能是有用的。免疫原性评估策略包括检测和表征结合抗体和中和抗体。检测方法基于使用 Biacore 3000 的表面等离子体共振生物传感器平台。在 Biacore 免疫测定中检测到结合抗体呈阳性的样品随后在中和测定中进行测试。接受罗米司亭治疗的 225 例免疫性血小板减少性紫癜（ITP）患者和 45 例接受安慰剂治疗的 ITP 患者的血清样本用于检测罗米司亭和 TPO 抗体。在接受罗米司亭治疗之前，有 17 名受试者（7%）检测到罗米司亭抗体阳性，12 名受试者（5%）检测到 TPO 抗体阳性，存在预先存在的结合抗体。在罗米司亭暴露后，11%的受试者表现出针对罗米司亭的结合抗体，5%的 ITP 受试者表现出针对 TPO 的结合抗体。针对罗米司亭的抗体与 TPO 没有交叉反应，反之亦然。在接受罗米司亭治疗的受试者中未检测到针对 TPO 的中和抗体。针对罗米司亭的中和抗体的发生率为 0.4%（1 例）；该受试者在 4 个月后的随访时检测结果为阴性。迄今为止，在具有罗米司亭抗体的受试者中，血小板谱没有明显变化。总之，在 ITP 受试者中给予罗米司亭导致针对罗米司亭和 TPO 配体产生结合抗体反应。有 1 例受试者对罗米司亭产生了中和抗体反应，影响了该受试者的血小板计数。未观察到针对内源性 TPO 的中和抗体。
