Targeting CD73 in the tumor microenvironment with MEDI9447
Carl M Hay, Erin Sult, Qihui Huang, Kathy Mulgrew, Stacy R Fuhrmann, Kelly A McGlinchey, Scott A Hammond, Raymond Rothstein, Jonathan Rios-Doria, Edmund Poon, Nick Holoweckyj, Nicholas M Durham, Ching Ching Leow, Gundo Diedrich, Melissa Damschroder, Ronald Herbst, Robert E Hollingsworth, Kris F Sachsenmeier, Carl M Hay, Erin Sult, Qihui Huang, Kathy Mulgrew, Stacy R Fuhrmann, Kelly A McGlinchey, Scott A Hammond, Raymond Rothstein, Jonathan Rios-Doria, Edmund Poon, Nick Holoweckyj, Nicholas M Durham, Ching Ching Leow, Gundo Diedrich, Melissa Damschroder, Ronald Herbst, Robert E Hollingsworth, Kris F Sachsenmeier
Abstract
MEDI9447 is a human monoclonal antibody that is specific for the ectoenzyme CD73 and currently undergoing Phase I clinical trials. Here we show that MEDI9447 is a potent inhibitor of CD73 ectonucleotidase activity, with wide ranging immune regulatory consequences. MEDI9447 results in relief from adenosine monophosphate (AMP)-mediated lymphocyte suppression in vitro and inhibition of mouse syngeneic tumor growth in vivo. In contrast with other cancer immunotherapy agents such as checkpoint inhibitors or T-cell agonists, MEDI9447 drives changes in both myeloid and lymphoid infiltrating leukocyte populations within the tumor microenvironment of mouse models. Changes include significant alterations in a number of tumor micro-environmental subpopulations including increases in CD8(+) effector cells and activated macrophages. Furthermore, these changes correlate directly with responder and non-responder subpopulations within animal studies using syngeneic tumors. Combination data showing additive activity between MEDI9447 and anti-PD-1 antibodies using human cells in vitro and mouse tumor models further demonstrate the potential value of relieving adenosine-mediated immunosuppression. Based on these data, a Phase I study to test the safety, tolerability, and clinical activity of MEDI9447 in cancer patients was initiated (NCT02503774).
Keywords: Adenosine; CD73; MEDI9447; monoclonal antibody; syngeneic tumor model; tumor microenvironment.
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Source: PubMed