TGF-β和PD-L1双靶向抗体Y101调节免疫微环境及抑制肿瘤的作用和机理研究

我国千万肿瘤患者对免疫治疗药品需求巨大，开发自主专利新药是国家战略。发现PD-1/PD-L1信号是肿瘤免疫的里程碑事件，其单抗抗癌谱广，但有效率低，且单一靶点易产生治疗耐药。TGF-β是肿瘤微环境中抑制免疫的重要因素，与PD-L1通路既相互独立又交互作用，共同促进免疫逃避。我们设想联合阻断肿瘤微环境中的TGF-β和PD-L1，既增加PD-L1单抗治疗效果又逆转其耐药性。基于自主专利技术平台，我们获得世界首个TGF-β/PD-L1双靶向抗体Y101。预实验结果显示Y101和两个靶点亲和力均高，稳定性好，体内抗瘤作用比PD-L1单抗强。然而Y101对肿瘤微环境的调控机制尚不清。本项目验证Y101双抗两端的生物学活性，综合评价其对肿瘤微环境中多种免疫细胞的影响，用移植瘤模型对比Y101较PD-L1单抗的优势。研究结果为克服PD-L1单抗的治疗耐药提供科学依据，并指导Y101临床病例的精准选择。

PD-1/PD-L1 is a vital signaling pathway participating in cancer immune evasion. The applications of anti-PD-1/PD-L1 antibodies are milestones of cancer immunotherapy. However, the main obstacles of anti-PD-1/PD-L1 antibodies in clinic are the low response rate in unselected patients and therapeutic resistance. The recent studies showed that overexpressed TGF-β was another immunosuppressive factor apart from traditional immune checkpoints. Actually, the effects of TGF-β and PD-1/PD-L1 pathways are independent and interactive, which work together leading to the immune evasion of cancer cell. ..We propose that blocking TGF-β and PD-L1 simultaneously could enhance the efficacy of PD-L1 monoclonal antibody and overcome its treatment resistance. Based on the advanced biotechnology platform Check-body developed by our collaborator, we designed the first TGF-β/PD-L1 bispecific antibody in the world named Y101. The results of pilot studies showed that Y101 had a high affinity to both TGF-β and PD-L1, good stability, and powerful anti-tumor effect than commercial anti-PD-L1 antibody in EMT-6 mouse model. However, the detailed mechanisms of immune modification and anti-tumor effect of Y101 in different mouse models are still unclear. ..This study will verify the biological activity of Y101 on signaling transduction of TGF-β and PD-L1. We also comprehensively evaluate the effect of Y101 on the tumor immune microenvironment. Besides, we will explore the advantages of Y101 over PD-L1 monoclonal antibody in various tumor models. Altogether, this project would substantially support technology platform for further development of bispecific antibody, provide preclinical evidence for overcoming the resistance of anti-PD-L1 monoclonal antibody treatment and guide the precise selection of cancer patient in the future clinical trial of Y101 bispecific antibody.