Development of Novel CD180-Based Cancer Immunotherapeutics

项目主任/主要研究者（最后，第一，中间）：克拉克，爱德华A 项目摘要 Abacus Bioscience专注于开发用于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， 即插即用的多种癌症或病毒抗原（Ags）。我们建议建立一个新的癌症类别 免疫治疗克服目前市售的检查点阻断抑制剂（CPI）的局限性 治疗许多癌症患者的免疫功能受到抑制;肿瘤的微环境可以积极地 促进免疫抑制。虽然一些癌症免疫疗法是非常有前途的， 重大限制。例如，基于PD-1的检查点CPI疗法仅诱导客观的临床疗效。 大约一半的癌症患者有反应。虽然它们可能会释放免疫系统的“刹车”， 如果没有抗原（Ag）特异性“点燃”和共刺激或先天免疫“激活”，它们不会促进 最佳的肿瘤免疫力我们的策略是克服目前癌症免疫治疗的障碍，特别是 不能对CPI疗法作出反应的患者，是将肿瘤相关的Ag靶向特异性活化的 免疫细胞。我们的免疫治疗剂既“激活”Ag特异性免疫应答，又“激活”强大的免疫应答， 协调的先天免疫我们已经发现，与CD 180特异性抗体（Ab）偶联的Ag （RP 105）受体（Ag-CD 180）诱导强烈的Ag特异性Ab和T细胞应答，并诱导保护性免疫。 致命的病毒感染将Ag靶向CD 180快速编程两种主要类型的Ag呈递细胞 （APCs）：树突状细胞（DC），激活免疫的“发令枪”APCs，和B细胞，维持免疫的APCs。 Ag特异性T细胞免疫。乳腺癌和卵巢癌等癌症中B细胞的存在与 预后更好。某些人类肿瘤中B细胞的存在与更好的反应性相关 免疫疗法基于CD 180的免疫治疗剂靶向并激活B细胞以成为 有效的APC提示基于CD 180的免疫系统可能能够激活肿瘤中的B细胞， 提高抗肿瘤免疫力。我们将测试我们的双重作用的CD 180为基础的免疫治疗是否可以单独工作 或与包括抗PD-1的其它免疫活化剂一起使用以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生存素（Survivin，Birc 5）蛋白作为肿瘤抗原，与抗 CD 180，以产生免疫球蛋白，生存素-CD 180。我们将设计并制备抗CD 180的Survivin 靶向小鼠或人CD 180的重组蛋白。我们将测试小鼠存活素-抗-CD 180是否可以 使用两种小鼠癌症模型预防、延迟或完全停止肿瘤生长。如果成功，这些研究 将建立一个新的癌症免疫治疗类别，并建立一个强大的临床前数据包， 将生存素-hCD 180免疫治疗剂转移到开发中并首先进行人体试验的基本原理。

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.