4-1BB抗体抗肿瘤活性和肝脏毒性的调控机理

共刺激受体的激动型抗体，能够增强T细胞的活化，是当前肿瘤免疫调控点抗体的重要补充，是肿瘤免疫治疗的重要方向。anti-4-1BB抗体，是其中的一个代表性共刺激受体激动型抗体，虽然其在临床前动物模型中显示了和免疫调控点抗体anti-PD1/anti-PD-L1相似的抗肿瘤活性，但是临床anti-4-1BB抗体的发展却远远落后于免疫调控点抗体，目前仅有两种4-1BB抗体进入了临床试验，分别面临不同的挑战，一个具有严重的肝脏毒副作用，另一个抗肿瘤效果较弱。本研究以人和鼠4-1BB抗体为对象，研究抗体的epitope和isotype以及宿主FcgR对抗肿瘤活性和肝脏毒性的调控机理。为临床发展高抗肿瘤活性，低肝脏毒性的anti-4-1BB抗体提供理论指导和先导分子。

Co-stimulation agonistic antibodies, aiming to push the gas paddle of T cell responses, are promising cancer immunotherapy candidates, adding to the recent success of immune checkpoint blockade antibodies to fight cancers. Agonist antibodies of co-stimulatory receptor 4-1BB showed robust anti-tumor activity in preclinical models, but their clinical development has been hampered by severe liver toxicity or low efficacy. Only two anti-4-1BB Abs have entered clinical trials: Urelumab and Utomilumab. These Abs face different challenges in the clinic: while safe, Utomilumab has relatively low efficacy, and Urelumab causes severe liver toxicity despite anti-tumor efficacy. We investigate how epitope- and isotype-dependent mechanisms contribute to the efficacy and toxicity of therapeutic anti-4-1BB antibodies. Manipulation of these characteristics may generate antibody candidates with favorable therapeutic profiles for cancer therapy.