寡核苷酸治疗剂(ONT)是一组不同的短合成的基于核酸的分子,其利用创新的细胞内分子策略来为各种医学病症创建新的治疗。ONT分子(〜7-15kDa)位于传统的大分子和小分子之间,关于它们的免疫原性风险一直存在争议。迄今为止,13种药物已被批准,由于该领域相对较新,目前没有具体的监管指导方针来指示如何制定,验证,并解释ONT的免疫原性测定。一些研究人员不测试对ON的免疫反应,而另一些研究人员测试制剂中成分的抗体(Abs)。其可以包括或可以不包括表征的方面,例如ONT缀合物的结构域映射。类似于其他生物制药,ONT的免疫原性可能受序列的影响,路线,剂量,目标人群,联合用药,等。目前不同批准的ONT的抗药物抗体(ADA)数据表明,它们的给药具有低免疫原性风险,对药代动力学(PK)没有任何重大影响。药效学(PD),和安全;尽管如此,直到该领域的数据来自更多的ON药物,评估免疫原性仍然是谨慎的。本文的重点是强调当前的ADA方法如何应用于ONT的开发,讨论可能造成免疫原性风险的因素,并提供作者对ONT免疫原性评估策略的当前立场。我们还讨论了可能适用于检测和表征ADAs的测定参数,包括中和ADAs的评估,ADA同种型,Abs到dsDNA,和预先存在的ADA。免疫原性风险评估(IRA)和与监管机构的早期相互作用将告知如何进行后期/关键研究。
Oligonucleotide therapeutics (ONTs) are a diverse group of short synthetic nucleic acid-based molecules that exploit innovative intracellular molecular strategies to create novel treatments for a variety of medical conditions. ONT molecules (~7-15 kDa) reside between traditional large and small molecules, and there has been debate regarding their immunogenicity risk. To date, 13 ON drugs have been approved, and as the field is relatively new, there are currently no specific regulatory guidelines to indicate how to develop, validate, and interpret the immunogenicity assays of ONTs. Some investigators do not test for immune responses to ONs while others test for antibodies (Abs) to components within the formulation, which may or may not include aspects of characterization such as domain mapping of ONT conjugates. Similar to other biopharmaceuticals, the immunogenic properties of ONTs could be influenced by sequence, route, dosage, target population, co-medications, etc. The current anti-drug antibody (ADA) data for different approved ONTs suggest that their administration poses a low immunogenicity risk without any significant impact on pharmacokinetics (PK), pharmacodynamics (PD), and safety; nevertheless, until the field matures with data from many more ON drugs, it remains prudent to assess immunogenicity. The emphasis of this article is to highlight how current ADA methodologies might be applied to the development of ONTs, discuss factors that may pose immunogenicity risks, and provide the authors\' current position on immunogenicity assessment strategies for ONTs. We also discuss assay parameters that may be appropriate for the detection and characterization of ADAs, including the evaluation of neutralizing ADAs, ADA isotyping, Abs to dsDNA, and pre-existing ADA. Immunogenicity risk assessments (IRAs) and early interactions with regulators will inform how to proceed in late stage/pivotal studies.