Development of Novel CD180-Based Cancer Immunotherapeutics

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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.