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

来源：

ONCOIMMUNOLOGY | 2016年 / 5卷 / 08期

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).

引用

页数：10

共 40 条

[1] Differential regulation and function of CD73, a glycosyl-phosphatidylinositol-linked 70-kD adhesion molecule, on lymphocytes and endothelial cells [J].