MNPR-101 is a novel, first-in-class humanized monoclonal antibody to the urokinase plasminogen activator receptor (uPAR), a well-characterized protein receptor that is constitutively over-expressed specifically by tumor cells.33 MNPR-101 has demonstrated significant anti-tumor activity in numerous preclinical models of tumor growth and is being advanced for clinical evaluation.20-22,26-32 Based on the expression of uPAR in a wide range of tumor tissues, and low expression in normal, healthy tissue, MNPR-101 is expected to be well-tolerated and amenable to a variety of combination treatment approaches.23,24
MNPR-101 was designed to interrupt several oncogenic signaling pathways required for tumor growth and progression that are only turned "on" in a tumor, rather than to kill the tumor cell directly.25 For this reason, Monopar believes that MNPR-101 may have fewer side effects than current cytotoxic agents which kill cells indiscriminately. In addition, by inhibiting multiple pathways required for tumor growth and progression, MNPR-101 may lead to more effective tumor control than therapies that target only a single such pathway. Monopar believes that most tumors, regardless of the tissue from which they originate, rely on the pathways that MNPR-101 is targeting.33 This type of therapy, which interferes with multiple critical pathways for tumor growth and progression, has the potential to be used against many different types of cancers.
MNPR-101 may also avoid some of the drug resistance problems caused by genetic instability that plague many conventional chemotherapies. Cancer cells mutate and reproduce rapidly, meaning that there is great genetic heterogeneity among cells in a tumor. A given chemotherapy may be effective against the vast majority of these cells, but if even a small number have mutations that confer resistance, these cells will likely survive the treatment. The tumor will grow back composed almost entirely of these mutated cells making the cancer resistant to further treatments with that particular chemotherapy. By targeting multiple tumor progression pathways, using drugs in combination regimens, and targeting more genetically stable endothelial and immune cells in addition to tumor cells, Monopar believes that MNPR-101 has the potential to avoid these drug resistance problems.
In addition to tumor cells, increased uPAR expression is observed in a wide variety of activated myeloid immune cells in response to bacterial and viral infection including monocytes, neutrophils, NK cells, and dendritic cells.35,36 uPAR expression in myeloid cells regulates their interaction with the extracellular matrix and their motility in diseased or damaged tissues.35 uPAR expression also mediates the production of pro-inflammatory cytokines in these cells. Increased levels of suPAR, the soluble form of uPAR, have been observed as part of the activation of the immune system in response to infection by a wide variety of pathogens including HIV-1, TB, and SARS-CoV2.34,36
High expression of the urokinase plasminogen activator receptor (uPAR) is a hallmark of the aberrant activation of myeloid cells that causes hyperinflammation and leads to shedding of suPAR from the myeloid cell surface. suPAR that circulates and can be measured in plasma is shed from the surface of neutrophils and macrophages in acute respiratory distress syndrome (ARDS) and correlates with the increased hyperimmune response mediated by these cells.37-39 suPAR levels correlate with inflammation and the severity and mortality of patients that develop ARDS and are prognostic for the development of ARDS in patients with sepsis.40 suPAR is also prognostic for ICU mortality in ARDS patients41, and a marker of infection in patients that develop acute kidney injury from the infection.42
A recently published study demonstrates that suPAR is an early predictor of severe respiratory failure in severe COVID-19 34. This increase in circulating suPAR is indicative of the aberrant activation of the immune system that leads to the cytokine storm responsible for the high degree of mortality observed in patients with severe COVID-19 who are managed with mechanical ventilation. Aberrantly activated immune cells have higher levels of uPAR expression on their surface than quiescent immune cells or non-immune adult tissues43, which makes uPAR an attractive drug target for the abrogation of the cytokine storm and treatment of patients with severe COVID-19.