Pipeline | Delta Opioid Receptor (DOR) Technology
DOR Technology and Bi-functional, bi-specific APCs and ADCs: Inhibiting MDSC immune suppressing functions
Tumor-associated Myeloid-derived suppressor cells (MDSCs)
MDSCs are among the most common cells present in the tumor microenvironment, which is the tissue surrounding the tumor, where they are a major regulator of suppression of the immune system. MDSCs are normally produced during pregnancy where they migrate to and populate the placenta, creating an immunologic sanctuary for the fetus. Since half of the genetic make-up of the fetus comes from the father, this is necessary to prevent the mother’s immune system from attacking the fetus. They are also produced in settings of chronic inflammation or autoimmune disease as a mechanism to decrease inflammation or autoimmunity. Under normal conditions MDSCs represent less than 2% of circulating peripheral blood mononuclear cells (PBMCs) and lack potent immune suppressing characteristics.
In cancer, MDSCs are hijacked by tumors and become highly immunosuppressive in the tissues in which the tumor lives. Multiple effector molecules and signaling pathways are used by MDSCs to regulate immune suppression. One main mechanism involves depletion of necessary amino acids like arginine through production of arginase (“Arg-1”), or “destruction” of inflammatory cytokines via production of inducible nitric oxide (“iNOS”), in addition to anti-inflammatory prostaglandins (“COX2”), immune suppressing cytokines like transforming growth factor beta (“TGFβ”) or Interleukin 10 (“IL-10”) and recruitment and induction of immune inhibitory cells such as regulatory T cells (T regs) . In addition to these mechanisms to affect T cell functionality, they also exert a direct effect on T cells, thereby inhibiting their proliferation. Accumulating evidence demonstrates that the enrichment and activation of MDSCs correlates with tumor progression, metastasis and recurrence. In addition, MDSCs circulating in the blood of patients with cancer is highly correlated to poor clinical outcomes.
Inhibiting and reprograming MDSC function represents a promising novel approach to overcome MDSC-induced tumor microenvironment immunosuppression and acquired resistance to cancer immunotherapies.
Delta Opioid Receptor (DOR) inhibitors: bi-specific, bi-functional antibody peptide or drug conjugates (APC, ADCs)
The DOR is the first cloned G protein-coupled receptor. Many recent studies on Delta Opioid Receptor functions have determined that the Delta Opioid Receptor is involved in the regulation of malignant transformation and tumor progression in multiple cancers.
While Delta Opioid Receptor overexpression and its role in tumor biology has been studied, we believe that TuHURA, along with scientists at Moffitt Cancer Center,
TuHURA, along with scientists at the Moffitt Cancer Center, are the first to describe the high differential expression of the Delta Opioid Receptor on tumor-associated MDSCs compared to bone marrow (BM) or spleen derived MDSCs in murine tumor bearing models.
As a previously unrecognized target to reprogram tumor associated MDSCs immunosuppressive functions on the tumor microenvironment, developing non-immunogenic peptidomimetic antagonists or small molecule antagonists with high specificity and avidity for the Delta Opioid Receptor represents a novel approach to reprograming MDSC functionality to overcome acquired resistance to checkpoint inhibitors and other cancer immunotherapies.
The Company anticipates utilizing TBS-2025, its VISTA inhibiting antibody, as the first APC or ADC to enter preclinical development.