Development of Novel CD180-Based Cancer Immunotherapeutics

基于 CD180 的新型癌症免疫疗法的开发

• 批准号: 10381384
• 负责人: Edward A Clark
• 金额: $ 39.8万
• 依托单位: ABACUS BIOSCIENCE INC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10381384
• 关键词: Adjuvant; Antibodies; Antibody Response; Antigen Targeting; Antigen-Presenting Cells; Antigens; Apoptosis Inhibitor; B-Lymphocytes; Binding; Biological Sciences; C-terminal; CAR T cell therapy; Cancer Model; Cancer Patient; Cells; Chronic; Clinical; Communicable Diseases; Control Groups; Coupled; Data; Dendritic Cells; Development; Doctor of Philosophy; Dose; Family; Gases; Glioblastoma; Goals; Guns; Human; Immune; Immune checkpoint inhibitor; Immune response; Immune signaling; Immune system; Immunity; Immunization; Immunize; Immunologic Deficiency Syndromes; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Knockout Mice; Legal patent; Malignant Neoplasms; Malignant neoplasm of ovary; Mature B-Lymphocyte; Measures; Molecular; Monoclonal Antibodies; Mus; Natural Immunity; Ovarian Carcinoma; Patients; Phase; Play; Principal Investigator; Prognosis; Proteins; Recombinant Fusion Proteins; Recombinant Proteins; Recombinants; Regimen; Serous; Side; Specificity; T cell anergy; T cell response; T-Lymphocyte; Technology; Testing; Therapeutic; Tumor Antigens; Tumor Immunity; Viral Antigens; Virus Diseases; West Nile virus; Work; anti-PD-1; antigen-specific T cells; base; cancer immunotherapeutics; cancer immunotherapy; cancer type; checkpoint therapy; design; env Gene Products; exhaustion; first-in-human; immune activation; immune checkpoint blockade; immunosuppressed; inhibitor; inhibitor therapy; malignant breast neoplasm; member; mouse model; nonhuman primate; novel; overexpression; pre-clinical; prevent; programmed cell death protein 1; programs; prophylactic; receptor; response; survivin; tumor; tumor growth; tumor microenvironment

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.

项目总监/首席研究员（最后、第一、中间）：Clark, Edward A 项目概要 Abacus Bioscience 专注于开发新颖且改变游戏规则的免疫疗法来治疗癌症 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 即插即用多种癌症或病毒抗原 (Ag)。我们建议建立一类新的癌症 免疫疗法克服目前上市的检查点阻断抑制剂（CPI）的局限性 疗法。许多癌症患者的免疫系统受到抑制；肿瘤的微环境可以主动 促进免疫抑制。尽管一些癌症免疫疗法非常有前途，但其他疗法却前景黯淡。 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 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“点火”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。我们克服当前癌症免疫治疗障碍的策略，特别是 对于无法对 CPI 疗法产生反应的患者，将肿瘤相关 Ag 靶向特异性激活 免疫细胞。我们的免疫疗法既可以“点燃”Ag特异性免疫反应，又可以“激活”强而有力的免疫反应。 协调先天免疫。我们发现 Ag 与 CD180 特异性抗体 (Ab) 偶联 (RP105) 受体 (Ag-CD180) 诱导强烈的 Ag 特异性 Ab 和 T 细胞反应以及对 a 致命的病毒感染。将 Ag 靶向 CD180 快速编程两大类 Ag 呈递细胞 (APC)：树突状细胞 (DC)，激活免疫力的“发令枪”APC，以及 B 细胞，维持免疫力的 APC Ag 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 具有更好的预后。某些人类肿瘤中 B 细胞的存在与更好的反应性相关 到免疫治疗。事实上，基于 CD180 的免疫疗法靶向并激活 B 细胞，使其成为 有效的 APC 表明基于 CD180 的免疫疗法可能能够激活肿瘤中的 B 细胞， 促进抗肿瘤免疫力。我们将测试基于 CD180 的双作用免疫疗法是否可以单独发挥作用 或与其他免疫激活剂（包括抗PD-1）结合以产生有效的抗肿瘤免疫力。我们有 选择生存素 (Birc5) 蛋白（凋亡抑制剂家族的成员）作为肿瘤 Ag 来偶联抗 CD180 用于创建免疫治疗药物 survivin-CD180。我们将设计和生产survivin-anti-CD180 靶向小鼠或人类 CD180 的重组蛋白。我们将测试小鼠survivin-anti-CD180是否可以 使用两种小鼠癌症模型来预防、延迟或完全阻止肿瘤生长。如果成功的话，这些研究 将建立一类新的癌症免疫疗法并建立强大的临床前数据包 将 survivin-hCD180 免疫疗法投入开发并首先进行人体测试的理由。