Development of Novel CD180-Based Cancer Immunotherapeutics

项目主任/首席调查员(最后、第一、中间)：克拉克、爱德华·A 项目总结 珠算生物科学专注于开发治疗癌症的新型和改变游戏规则的免疫疗法 和慢性传染病。我们开发了一种基础广泛的专利平台技术，可以 即插即用的多种癌症或病毒抗原(AGS)。我们建议设立一种新的癌症类别 克服目前市场上销售的检查点阻断抑制剂(CPI)局限性的免疫疗法 治疗。许多癌症患者免疫功能受到抑制；肿瘤的微环境可以 促进免疫抑制。尽管一些癌症免疫疗法很有前途，但另一些 明显的局限性。例如，基于PD-1的检查点CPI疗法只能诱导客观的临床 大约一半的癌症患者有反应。尽管它们可能会释放免疫系统的“刹车”， 如果没有抗原(Ag)特异性的“点燃”和共刺激或天然免疫“激活”，它们就不会促进 最佳的肿瘤免疫力。我们克服目前癌症免疫治疗障碍的战略，特别是针对 对CPI治疗无效的患者，是针对肿瘤相关的AGS进行特异性激活 免疫细胞。我们的免疫疗法既有“Ignite”抗原特异性免疫反应，又有“Activate”强大和 协调的先天免疫力。我们发现抗原与CD180的特异性抗体偶联 (RP105)受体(Ag-CD180)诱导抗原特异性抗体和T细胞应答及保护性免疫 致命的病毒感染。将AGS靶向CD180快速编程两类主要的Ag提呈细胞 (APC)：树突状细胞(DC)，激活免疫的“发令枪”APC，以及B细胞，维持 抗原特异性T细胞免疫。B细胞在乳腺癌和卵巢癌等癌症中的存在与 预后较好。B细胞在某些人类肿瘤中的存在与更好的反应性相关 去接受免疫治疗。以CD180为基础的免疫疗法靶向并激活B细胞成为 高效的APC表明，基于CD180的免疫疗法可能能够激活肿瘤中的B细胞和 促进抗肿瘤免疫。我们将测试我们的基于CD180的双作用免疫疗法是否可以单独奏效 或与包括抗PD-1在内的其他免疫激活剂一起产生有效的抗肿瘤免疫。我们有 选择凋亡抑制因子家族成员Survivin(Birc5)蛋白作为肿瘤抗原偶联抗-HBs。 CD180产生免疫治疗性Survivin-CD180。我们将设计和生产Survivin-抗CD180 以鼠或人CD180为靶点的重组蛋白。我们将测试小鼠Survivin-抗CD180是否可以 使用两种小鼠癌症模型预防、延缓或完全阻止肿瘤生长。如果成功，这些研究 将建立新的癌症免疫疗法类别，并建立强大的临床前数据包和 将Survivin-hCD180免疫疗法转移到开发中并首次用于人体测试的基本原理。

Program Director/Principal Investigator (Last, First, Middle): Clark, Edward A PROJECT SUMMARY Abacus Bioscience focuses on developing novel and game changing immunotherapies for treating cancers and chronic infectious diseases. We have developed a broad-based, patented, platform technology that can plug-and-play with multiple cancer or viral antigens (Ags). We propose to establish a new class of cancer immunotherapeutics to overcome the limitations of currently marketed checkpoint blockade inhibitor (CPI) therapies. Many patients with cancers are immunosuppressed; the microenvironment of tumors can actively promote immunosuppression. Although some cancer immunotherapies are quite promising, others have significant limitations. PD-1-based checkpoint CPI therapies, for example, only induce objective clinical responses in about half of cancer patients. Although they may release the `Brake' on the immune system, without antigen (Ag)-specific `Ignition' and co-stimulation or innate immune `Activation', they do not promote optimal tumor immunity. Our strategy to overcome current obstacles to cancer immunotherapy, particularly for patients who are unable to respond to CPI therapies, is to target tumor-associated Ags to specifically-activated immune cells. Our immunotherapeutics both `Ignite' Ag-specific immune responses and `Activate' strong and coordinated innate immunity. We have found that Ags coupled to antibodies (Abs) specific for the CD180 (RP105) receptor (Ag-CD180) induce strong Ag-specific Ab and T cell responses and protective immunity to a lethal viral infection. Targeting Ags to CD180 rapidly programs two major classes of Ag presenting cells (APCs): dendritic cells (DCs), the `starting gun' APCs that activate immunity, and B cells, APCs that sustain Ag-specific T cell immunity. The presence of B cells in cancers such as breast and ovarian cancers correlates with a better prognosis. The presence of B cells in certain human tumors correlates with better responsiveness to immunotherapy. The fact that CD180-based immunotherapeutics target and activate B cells to become efficient APCs suggests that a CD180-based immunotherapeutic may be able to activate B cells in tumors and promote anti-tumor immunity. We will test if our dual-action CD180-based immunotherapeutics can work alone or with other immune activators including anti-PD-1 to produce effective anti-tumor immunity. We have selected the survivin (Birc5) protein, a member of inhibitor of apoptosis family, as a tumor Ag to couple to anti- CD180 to create the immunotherapeutic, survivin-CD180. We will design and produce survivin-anti-CD180 recombinant proteins that target either mouse or human CD180. We will test if mouse survivin-anti-CD180 can prevent, delay or completely stop tumor growth using two mouse cancer models. If successful, these studies will establish a new class of cancer immunotherapeutics and build a strong preclinical data package and rationale for moving survivin-hCD180 immunotherapeutics into development and first in human testing.