Program Director/Principal Investigator (Last, First, Middle): Clark, Edward A 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-CD180recombinant proteins that target either mouse or human CD180. We will test if mouse survivin-anti-CD180 canprevent, 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.
Public Health Relevance Statement: Program Director/Principal Investigator (Last, First, Middle): Clark, Edward A.
Project narrative: Project Title: Development of Novel CD180-Based Cancer Immunotherapeutics Organization: Abacus Bioscience Inc. PI: Edward A. Clark, Ph.D. Co-PI: Deborah H. Fuller, Ph.D. While some cancer immunotherapies are quite promising, others have noteworthy limitations; checkpoint blockade inhibitor (CBI) therapies, for example, only induce objective clinical responses in about half of cancer patients. Using a novel patented platform technology, we propose to develop a new class of cancer immunotherapeutics that will induce potent therapeutic immune responses to human cancers expressing the protein survivin. We will test if our recombinant protein immunotherapeutic can prevent, delay or completely stop tumor growth using two mouse cancer models.
Project Terms: inhibitor, Antibodies, Monoclonal Antibodies, Clinical Treatment Moab, mAbs, Antigen-Presenting Cells, accessory cell, Antigens, immunogen, Viral Antigens, virus antigen, B-Lymphocytes, B blood cells, B cell, B cells, B-Cells, B-cell, Biological Sciences, Biologic Sciences, Bioscience, Life Sciences, malignant breast neoplasm, Breast Cancer, malignant breast tumor, Malignant Neoplasms, Cancers, Malignant Tumor, malignancy, neoplasm/cancer, Cells, Cell Body, Communicable Diseases, Infectious Disease Pathway, Infectious Diseases, Infectious Disorder, Control Groups, Dendritic Cells, Veiled Cells, Family, Gases, env Gene Products, Envelope Protein, env Antigens, env Polyproteins, env Protein, Glioblastoma, Grade IV Astrocytic Neoplasm, Grade IV Astrocytic Tumor, Grade IV Astrocytoma, glioblastoma multiforme, spongioblastoma multiforme, Goals, Guns, gun, Human, Modern Man, Immune system, allergic/immunologic body system, allergic/immunologic organ system, Immunity, Natural Immunity, Innate Immunity, Native Immunity, Non-Specific Immunity, Nonspecific Immunity, Immunization, Immunologic Sensitization, Immunologic Stimulation, Immunological Sensitization, Immunological Stimulation, Immunostimulation, Immunologic Deficiency Syndromes, Immunodeficiency Disorder, Immunodeficiency Syndrome, Immunological Deficiency Syndromes, hypoimmunity, immune deficiency disorder, immunodeficiency, Immunosuppression, Immunosuppression Effect, Immunosuppressive Effect, immune suppression, immune suppressive activity, immune suppressive function, immunosuppressive activity, immunosuppressive function, Immunotherapy, Immune mediated therapy, Immunologically Directed Therapy, immune therapeutic approach, immune therapeutic interventions, immune therapeutic regimens, immune therapeutic strategy, immune therapy, immune-based therapies, immune-based treatments, immuno therapy, Mus, Mice, Mice Mammals, Murine, Ovary Carcinoma, Ovarian Carcinoma, Patents, Legal patent, Patients, Play, Proteins, Recombinant Fusion Proteins, Recombinant Proteins, Specificity, T-Cells, thymus derived lymphocyte, T-Lymphocyte, Technology, Testing, Tumor Antigens, Tumor-Associated Antigen, cancer antigens, tumor-specific antigen, Virus Diseases, Viral Diseases, viral infection, virus infection, virus-induced disease, West Nile virus, Egypt 101 virus, WNV, West Nile, Work, Measures, base, Chronic, Clinical, Phase, KO mice, Knock-out Mice, Null Mouse, Knockout Mice, non-human primate, nonhuman primate, anti-cancer immunotherapy, anticancer immunotherapy, immune-based cancer therapies, immunotherapy for cancer, immunotherapy of cancer, cancer immunotherapy, Immunological response, host response, immune system response, immunoresponse, Immune response, Therapeutic, programs, exhaustion, Immunes, Immune, Serous, Side, prophylactic, Receptor Protein, receptor, tumor growth, Apoptosis Inhibitor 4, Apoptosis Inhibitor Survivin, Baculoviral IAP Repeat-Containing Protein 5, survivin, novel, member, response, immune drugs, immune-based therapeutics, immunologic preparation, immunologic therapeutics, immunotherapeutics, immunotherapy agent, Immunotherapeutic agent, Malignant Ovarian Neoplasm, Malignant Ovarian Tumor, Malignant Tumor of the Ovary, Ovary Cancer, ovarian cancer, Malignant neoplasm of ovary, Molecular Interaction, Binding, preventing, prevent, Apoptosis Inhibitor Gene, Apoptosis Inhibitor, PD 1, PD-1, PD1, programmed cell death 1, programmed death 1, sle2, systemic lupus erythematosus susceptibility 2, programmed cell death protein 1, Dose, Data, Ph.D., PhD, Doctor of Philosophy, Mature B-Cell, Mature B-Lymphocyte, Recombinants, Antigen Targeting, Cancer Model, CancerModel, Cancer Patient, Tumor Immunity, anti-tumor immunity, antitumor immunity, cancer immunity, Principal Investigator, Molecular, Adjuvant, Development, developmental, pre-clinical, preclinical, T cell anergy, tumor microenvironment, cancer microenvironment, immunosuppressed, design, designing, cancer type, Coupled, C-terminal, mouse model, murine model, tumor, overexpression, overexpress, Regimen, T cell response, immune activation, Immune Cell Activation, Antibody Response, checkpoint therapy, check point immunotherapy, check point inhibitor therapy, check point inhibitory therapy, check point therapy, checkpoint immunotherapy, checkpoint inhibitor therapy, checkpoint inhibitory therapy, immune check point therapy, immune checkpoint therapy, Immune signaling, immune checkpoint blockade, check point blockade, checkpoint blockade, immune check point blockade, Immune checkpoint inhibitor, Checkpoint inhibitor, immune check point inhibitor, Immunize, antigen-specific T cells, anti-PD-1, aPD-1, aPD1, anti programmed cell death 1, anti-PD1, anti-programmed cell death protein 1, antiPD-1, antiPD1, αPD-1, αPD1, first-in-human, first in man, CAR T cell therapy, CAR T therapy, chimeric antigen receptor (CAR) T cell therapy, chimeric antigen receptor T cell therapy, cancer immunotherapeutics, cancer immune therapeutics, Prognosis, inhibitor therapy, inhibitor drug, inhibitor therapeutic
