基于液滴微流控系统高通量筛选共刺激受体OX40的激动剂抗体

Both antagonist antibody of checkpoint or agonist of costimulatory receptor can boost immune response of T cells in cancer immunotherapy. The early overseas clinical trial data of these agonists demonstrated potential anti-tumor activity, indicating agonist antibody of costimulatory receptor is worth more attention in China. However, it is difficult to discover agonist antibody using the conventional screening methods. To overcome this challenge, we will develop a high-throughput method for screening agonist antibody using droplet-based microfluidics. We will screen agonist antibody of costimulatory receptor OX40. The selected antibodies are subject to immunological pharmacology and structural biology studies and the relationship between affinity and efficacy of agonist antibody of costimulatory receptor is also to be studied. The innovative method can contribute to the more efficient development of agonist antibody candidates and lead to promising cancer immunotherapy.

肿瘤免疫疗法中，免疫检查点的拮抗剂抗体和共刺激受体的激动剂抗体均是增强肿瘤特异性T细胞反应的有效策略。共刺激受体的激动剂抗体在国外临床试验中已取得一些令人鼓舞的数据，这类药物的研发值得引起国内重视。激动剂抗体的筛选非常困难，限制了激动剂抗体药物的发展。针对这个问题，我们首先基于液滴微流控系统建立激动剂抗体的高通量筛选方法。接下来我们将应用该方法筛选共刺激受体OX40的激动剂抗体并进一步对候选抗体进行免疫药理学和结构生物学研究以阐明其药物作用机制。该项目也将首次研究共刺激受体激动剂抗体的亲和力和药效的关系。高效的共刺激受体激动剂抗体筛选方法将有助于国内外业界和学术界更高效地开发共刺激受体的激动剂抗体，为肿瘤免疫疗法提供更多的弹药。

制药界缺少直接基于活性而非单纯依靠结合力分离抗体的高通量方法。针对这个问题，我们开发了一种高效的基于液滴微流体系统的筛选平台，该平台结合了慢病毒转导系统和液滴微流控系统，能够对数百万抗体进行功能筛选。我们使用该平台快速的发现了具有强激活活性的OX40激动剂和CD40激动剂抗体。其中一个全人源OX40激动剂抗体在体外促进T细胞活化和增殖并在肿瘤小鼠模型中显示出相对国外同类抗体更有效的抗肿瘤活性。该抗体亲和力和效力之间的关系研究显示虽然激动剂抗体的亲和力成熟版本在体外显示出更强的对报告细胞的激活活性，但在小鼠模型中失去了肿瘤抑制活性。因此，在I期临床试验（NCT05229601）中，我们选择具有中等亲和力的OX40激动剂抗体对晚期实体瘤的成年患者进行评估。