The goal of this application is to evaluate the cancer therapeutic feasibility of CanCure's humanized first-in- class immunostimulatory monoclonal antibody (mAb) huB10G5 (the Product, also names CuraB10). During cancer development, in response to oncogenic insult or stress, almost ALL human cancer cells are induced to express a SURFACE molecule MIC (MHC I chain-related Molecule) which deems to alert and ignite the immune defense machinery to eliminate cancers. However, this innate power of cancer control was disabled in cancer patients, because human cancer cells evolved to shed the surface MIC and release soluble MIC (sMIC) into the circulation. sMIC is highly immune suppressive and hijacks the immune systems to allow cancers to progression. We have developed a mouse mAb B10G5 that neutralizes sMIC but does not block the interaction of tumor cell-bound MIC with its immunoactivating receptor NKG2D. Pre-clinical studies in animal models have demonstrated that B10G5 stand-alone therapy remarkably induced regression (>80%) of spontaneous advanced primary tumors and eliminated metastasis, even in tumors that are non-responsive to current immune checkpoint blockade therapy. B10G5 therapy also enhanced responses to immune checkpoint blockade therapies, when used in combination. Mechanistically, B10G5 therapy not only eliminates the immune suppression of sMIC but also invigorates endogenous anti-tumor immune responses through novel mechanisms. CanCure has humanized B10G5. In this Phase I application, we propose to evaluate the therapeutic feasibility the two huB10G5 leading candidates with Specific Aims: 1) to evaluate whether a huB10G5 has comparable therapeutic efficacy and stability to the parental mouse B10G5 using our established in vitro and in vivo assays; 2) to assess the risk of unwanted ADA (anti-drug antibody) immunogenicity of the huB10G5 candidates using well established in vitro DC-T assay. Completion of these tasks is critical for CanCure to justify the milestones for Phase II product development towards commercialization. The outcome will have direct impact on the survival of cancer patients. The proposed study will be accomplished through a collaboration of CanCure with the Medical University of South Carolina, the academic partner.
In this STTR Phase I application, we propose to evaluate the therapeutic feasibility of our humanized first-in-class cancer immunotherapeutic antibody, in partnership with the Medical University of South Carolina. The proposed study is critical for justifying the milestones of the next Phase of product development. The outcome will directly benefit a board type of cancer patients with advanced diseases, including those who failed to respond to current available immunotherapies.
|Dhar, Payal; Wu, Jennifer D (2018) NKG2D and its ligands in cancer. Curr Opin Immunol 51:55-61|
|Zhang, Jingyu; Liu, Dai; Li, Guangfu et al. (2017) Antibody-mediated neutralization of soluble MIC significantly enhances CTLA4 blockade therapy. Sci Adv 3:e1602133|