Targeting CD73 in the tumor microenvironment with MEDI9447

被引:247
作者
Hay, Carl M. [1 ]
Sult, Erin [1 ]
Huang, Qihui [1 ]
Mulgrew, Kathy [1 ]
Fuhrmann, Stacy R. [1 ]
McGlinchey, Kelly A. [1 ]
Hammond, Scott A. [1 ]
Rothstein, Raymond [1 ]
Rios-Doria, Jonathan [1 ]
Poon, Edmund [2 ]
Holoweckyj, Nick [1 ]
Durham, Nicholas M. [1 ]
Leow, Ching Ching [3 ]
Diedrich, Gundo [4 ]
Damschroder, Melissa [1 ]
Herbst, Ronald [1 ]
Hollingsworth, Robert E. [1 ]
Sachsenmeier, Kris F. [1 ]
机构
[1] MedImmune LLC, Gaithersburg, MD USA
[2] MedImmune LLC, MedImmune, Cambridge, England
[3] Astrazeneca, Gaithersburg, MD USA
[4] MacroGenics Inc, Macrogen, Rockville, MD USA
关键词
Adenosine; CD73; MEDI9447; monoclonal antibody; syngeneic tumor model; tumor microenvironment; T-CELL INFILTRATION; CANCER-IMMUNOTHERAPY; ADENOSINE; ANTIBODY; THERAPY; INHIBITION; PROTECTS; MOLECULE; MELANOMA; ADHESION;
D O I
10.1080/2162402X.2016.1208875
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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).
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