Global Research, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapeutics, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
Sci Transl Med. 2017 Jan 11;9(372). doi: 10.1126/scitranslmed.aag1286.
Immunogenicity is an important consideration in the licensure of a therapeutic protein because the development of neutralizing anti-drug antibodies (ADAs) can affect both safety and efficacy. Neoantigens introduced by bioengineering of a protein drug are a particular cause for concern. The development of a bioengineered recombinant factor VIIa (rFVIIa) analog was discontinued after phase 3 trials because of the development of ADAs. The unmodified parent molecule (rFVIIa), on the other hand, has been successfully used as a drug for more than two decades with no reports of immunogenicity in congenital hemophilia patients with inhibitors. We used computational and experimental methods to demonstrate that the observed ADAs could have been elicited by neoepitopes in the engineered protein. The human leukocyte antigen type of the patients who developed ADAs is consistent with this hypothesis of a neoepitope-driven immune response, a finding that might have implications for the preclinical screening of therapeutic protein analogs.
免疫原性是治疗性蛋白获得许可的一个重要考虑因素，因为中和性抗药物抗体 (ADA) 的产生可能会影响安全性和疗效。蛋白质药物的生物工程引入的新抗原尤其令人担忧。由于 ADA 的产生，一种经过生物工程改造的重组因子 VIIa (rFVIIa) 类似物在 3 期临床试验后被停止开发。另一方面，未经修饰的母体分子 (rFVIIa) 已经成功地作为药物使用了二十多年，在没有抑制剂的先天性血友病患者中没有免疫原性的报告。我们使用计算和实验方法证明，观察到的 ADA 可能是由工程蛋白中的新表位引起的。产生 ADA 的患者的人类白细胞抗原类型与这种新表位驱动免疫反应的假设一致，这一发现可能对治疗性蛋白类似物的临床前筛选具有重要意义。
