Preclinical Sciences & Translational Safety, Janssen R&D LLC, Spring House, Pennsylvania, 19477, USA.
AAPS J. 2022 Aug 26;24(5):93. doi: 10.1208/s12248-022-00741-x.
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.
寡核苷酸疗法（ONTs）是一组多样化的短合成核酸分子，利用创新的细胞内分子策略为各种医疗状况创造新的治疗方法。ONT 分子（~7-15 kDa）位于传统的大分子和小分子之间，关于其免疫原性风险一直存在争议。迄今为止，已有 13 种 ON 药物获得批准，由于该领域相对较新，目前尚无特定的监管指南来指示如何开发、验证和解释 ONTs 的免疫原性检测。一些研究人员不检测对 ON 的免疫反应，而另一些则检测制剂中成分的抗体（Abs），这些 Abs 可能包括或不包括 ON 缀合物的特征分析等方面。与其他生物制药类似，ONTs 的免疫原性特性可能受序列、途径、剂量、目标人群、合并用药等因素的影响。不同批准的 ONTs 的当前抗药物抗体（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）、药效学（PD）和安全性没有任何重大影响；然而，在该领域随着更多 ON 药物的数据成熟之前，评估免疫原性仍然是谨慎的。本文的重点是强调如何将当前的 ADA 方法应用于 ONTs 的开发，讨论可能构成免疫原性风险的因素，并提供作者对 ONTs 免疫原性评估策略的当前立场。我们还讨论了可能适用于 ADA 检测和特征分析的检测参数，包括中和 ADA 的评估、ADA 分型、双链 DNA 抗体和预先存在的 ADA。免疫原性风险评估（IRAs）和与监管机构的早期互动将告知如何在后期/关键研究中进行。
