兼具I型和II型CD20抗体抗肿瘤优势的新型CD20抗体抗肿瘤机理研究

Although CD20 monoclonal antibodies (mAbs) have succeeded in lymphoma treatment and have been widely used for the treatment of B-cell malignancies, the acquired resistance is one of the prime obstacles for cancer treatment, and development of novel CD20-targeting antibodies with potent anti-tumor activities and specificities is urgently needed. CD20 antibodies are usually defined as either type I or II, based on their ability against lymphoma. Type I mAbs (rituximab and most anti-CD20 mAbs) are able to induce potent CDC and low level of cell death, whereas type II mAbs are relatively inactive in complement activation but tend to promote more cell death. Both type I and type II CD20 mAbs have exhibited advantages against lymphoma, but until now there is not a CD20 mAb with the benefits of both type I and type II CD20 mAbs that has been reported. In our previous studies, we have identified a mutation located at the complementarity determining region of Rituximab heavy chain, which has been demonstrated to have the ability to endow rituximab with the advantages of both type I and type II CD20 mAbs. Here, we will systematically investigate the correlation between the antibody binding epitope structures and the anti-tumor efficacy. Based on theses findings, we will characterize novel CD20 antibodies with the benefits of both type I and type II CD20 mAbs and potent anti-tumor activities against lymphoma. Then, the role of potent caspase-independent cell death induced by the novel CD20 antibody in induction of tumor-specific immunity will be explored. This study would help us deeply understand the correlation between the antibody binding epitope structures and its anti-tumor efficacy, which would provide a solid foundation for development of novel CD20 antibodies with more potent anti-tumor activities against lymphoma.

虽然CD20抗体Rituximab已被广泛用于淋巴瘤临床一线治疗，是目前疗效较好的抗体靶向药物，但是大部分患者会逐渐产生复发和耐受。迫切需要设计更好的抗体药物用于淋巴瘤的临床治疗。根据其功能可将CD20抗体分为I型和II型CD20抗体，其在临床治疗中各有优势，但是目前尚无兼具I型和II型CD20抗体优势的新型抗体被报道。本研究拟将基于我们前期研究发现的能够使Rituximab兼具I型和II型CD20抗体优势的一个点突变入手，借助计算机模拟等方法深入研究Rituximab抗体空间表位结构与其抗肿瘤活性的关系。在此基础上，鉴定出具有更好抗肿瘤活性、兼具I型和II型CD20抗体优势的新型CD20抗体，并系统研究该抗体诱导的非caspase依赖细胞死亡在抗体激活抗肿瘤免疫中的作用。本研究为深入理解靶向抗体表位空间结构与其抗肿瘤活性的关系，后续设计具有更好抗肿瘤活性的新型CD20抗体奠定基础。

靶向抗体由于特异性高、副作用小、半衰期长等优势，已广泛应用于临床疾病诊疗。抗体的结合位点和亲和力被认为是影响抗体活性的主要影响因素。然而，在不改变抗体亲和力和结合位点的情况下，我们发现在Rituximab上仅一个点突变可以使得Rituximab获得诱导细胞死亡的能力。进一步的研究表明，Rituximab上该位点的突变（H102YK）很可能与CD20靶蛋白179的Ser形成相互作用进而使得其获得细胞死亡诱导能力。在我们发现兼具I型和II型CD20抗体优势的新型CD20抗体被发现后，多个研究团队陆续报道了新型CD20抗体的存在，该新型CD20抗体最终被定义为III型CD20抗体。此项研究表明，蛋白-蛋白相互作用能显著影响蛋白功能。在此基础上，我们借助分子动力学模拟与蛋白结构生物学分析系统分析了蛋白-蛋白相互作用规律。借助计算生物学和人工智能新技术，建立了基于靶蛋白结构直接设计超高亲和力结合蛋白的技术平台。后续针对新冠和PD-L1设计获得超高亲和力结合蛋白，且表现出比抗体更高的亲和力、更小的分子量和更高的稳定性，有望成为未来新一代靶向蛋白技术。该项目获科技部组织的全国颠覆性技术创新大赛优胜项目奖。