Advanced Solid Cancers and Severe COVID-19

MNPR-101, as a first-in-class anti-uPAR humanized monoclonal antibody, represents a potentially selective means for delivering cytotoxic agents to aberrantly activated cells. Conjugation of MNPR-101 to a radionuclide, for example Actinium-225, may produce a potent and selective cytotoxic agent with wide applicability for the imaging and treatment of advanced solid cancers and severe COVID-19. Monopar, in collaboration with NorthStar Medical Radioisotopes, is pursuing development of a MNPR-101 RIT for these indications.  

Inflammation

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.

The ubiquitous expression of uPAR on activated immune cells, and its central importance in chemotaxis, invasion and recognition, makes uPAR a very attractive drug target in a wide variety of inflammatory indications, including bacterial and viral infection. MNPR-101, as a first-in-class anti-uPAR humanized monoclonal antibody, represents a selective means for delivery of cytotoxic agents to hyperactive immune cells. Conjugation of MNPR-101 to a radionuclide would produce a potent and selective cytotoxic agent, with applicability to a wide range of inflammatory indications.

One such indication is severe COVID-19. By targeting aberrantly activated immune cells in severe COVID-19 patients, the risk of a lethal cytokine storm could be significantly reduced. Such a radio-immuno-therapeutic (RIT) would constitute a powerful new therapeutic tool, with the potential to drastically reduce the burden of disease and mortality incidence of COVID-19. Monopar, in collaboration with NorthStar Medical Radioisotopes, an industry-leading producer of medical radionuclides, is pursuing accelerated development of such an RIT, based on MNPR-101.