Oleclumab (MEDI9447): A Comprehensive Monograph on a Novel Anti-CD73 Immunotherapy

Executive Summary

Oleclumab (development code: MEDI9447) is an investigational, human IgG1λ monoclonal antibody developed by AstraZeneca that targets the ectoenzyme CD73, a novel immune checkpoint. The drug's mechanism of action is centered on inhibiting the production of immunosuppressive adenosine within the tumor microenvironment (TME). By blocking the enzymatic conversion of adenosine monophosphate (AMP) to adenosine, Oleclumab is designed to reverse adenosine-mediated immune cell suppression, thereby enhancing the body's innate anti-tumor immune response. This involves increasing the activity of cytotoxic CD8+ T cells and macrophages while reducing the populations of regulatory T cells and myeloid-derived suppressor cells.

The clinical development of Oleclumab has been characterized by a sharp dichotomy of outcomes. The most significant promise for the drug lies in its potential application for unresectable, Stage III non-small cell lung cancer (NSCLC) following concurrent chemoradiation (cCRT). The Phase II COAST trial demonstrated that the combination of Oleclumab with the PD-L1 inhibitor durvalumab resulted in clinically meaningful and statistically significant improvements in objective response rate and progression-free survival compared to durvalumab monotherapy, the current standard of care. These encouraging results have led to the initiation of the large-scale, potentially registrational Phase III PACIFIC-9 trial, the outcome of which will be the primary determinant of Oleclumab's future.