Early prediction of formulation behaviour for new antibody products

基于抗体的生物制剂，如单克隆抗体（mAb），由于其独特的治疗潜力，是生物制药行业快速增长的部分。预计到2022年，基于抗体的治疗剂的全球市场将达到1146亿美元，从2017年到2022年的复合年增长率（CAGR）为6.3%（Dewan，2017）。与传统的小分子药物相比，mAb具有高水平的特异性和低毒性特征，这促使它们成功靶向先前无法治疗的适应症（Keizer et al，2010）。因此，开发新型mAb疗法和生物仿制药的研究兴趣不断增加。由于对经济有效地配制治疗药物以安全递送给患者的需求很高，因此制剂开发仍然是mAb生产的主要挑战。这些大分子的复杂性增加使得它们更不稳定并且易于化学和/或物理降解，因此需要特殊的处理和储存。冻干或冷冻干燥是工业中常用的方法，用于保存mAb的化学和生物学特性，以维持长期稳定性并延长保质期（Carpenter et al，2002）。蛋白质聚集是一个常见的问题，可能发生在任何阶段的生产过程中，直到药物管理。聚集不仅会影响蛋白质功能并降低产物产率，还会缩短治疗半衰期并在患者中引起免疫原性反应（Wang et al，2007）SPEL的既往工作揭示了自相互作用色谱（SIC）获得的渗透第二维里系数（B22）与mAb聚集倾向之间的关系（Hedberg et al，2018）。该项目的目的是进一步研究液体和冻干生物治疗药物的聚集倾向，并了解聚集机制，以帮助预测新型mAb的聚集趋势。除了广泛的结构表征外，还将研究功能性以评估生物活性和免疫原性。

Antibody-based biologics such as monoclonal antibodies (mAbs) are a fast-growing segment of the biopharmaceutical industry due to their distinctive therapeutic potential. The global market for antibody-based therapeutics is forecasted to reach $114.6 billion by 2022 growing at a compound annual growth rate (CAGR) of 6.3% from 2017 to 2022 (Dewan, 2017). In contrast to traditional small molecule drugs, mAbs have high levels of specificity with low toxicity profiles, which drives their success in targeting previously untreatable indications (Keizer et al, 2010). Consequently, there has been a rise in research interest in developing novel mAb therapies and biosimilars.Formulation development remains a major challenge in mAb production as there is a high demand to formulate therapeutics economically and effectively for safe delivery to patients. The increased complexity of these large molecule makes them more unstable and prone to chemical and/or physical degradation, therefore requiring special handling and storage. Lyophilisation, or freeze drying is a common method used in industry to preserve chemical and biological properties of mAbs to sustain long-term stability and improve shelf life (Carpenter et al, 2002). Protein aggregation is a common problem that can occur at any stage of the manufacturing process up until drug administration. Not only can aggregation affect protein function and decrease product yield, it can also reduce the therapeutic half-life and cause immunogenic reactions in patients (Wang et al, 2007).Previous work at SPEL have uncovered the relationship between the Osmotic second virial coefficient (B22) obtained from self-interaction chromatography (SIC) and propensity of mAb aggregation (Hedberg et al, 2018). The aim of the project is to further investigate aggregation propensity of liquid and lyophilised biotherapeutics and understand the mechanisms of aggregation to help predict aggregation tendencies of novel mAbs. In addition to extensive structural characterisation, functionality will be investigated to assess biological activity and immunogenicity.