Targeting CD73 in the tumor microenvironment with MEDI9447.
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).
MedImmune, LLC , Gaithersburg, MD, USA.
Carl M
CM
Hay
MedImmune, LLC , Gaithersburg, MD, USA.
Erin
E
Sult
MedImmune, LLC , Gaithersburg, MD, USA.
Qihui
Q
Huang
MedImmune, LLC , Gaithersburg, MD, USA.
Kathy
K
Mulgrew
MedImmune, LLC , Gaithersburg, MD, USA.
Stacy R
SR
Fuhrmann
MedImmune, LLC , Gaithersburg, MD, USA.
Kelly A
KA
McGlinchey
MedImmune, LLC , Gaithersburg, MD, USA.
Scott A
SA
Hammond
MedImmune, LLC , Gaithersburg, MD, USA.
Raymond
R
Rothstein
MedImmune, LLC , Gaithersburg, MD, USA.
Jonathan
J
Rios-Doria
Medimmune, LLC, MedImmune , Cambridge, UK.
Edmund
E
Poon
MedImmune, LLC , Gaithersburg, MD, USA.
Nick
N
Holoweckyj
MedImmune, LLC , Gaithersburg, MD, USA.
Nicholas M
NM
Durham
Astrazeneca , Gaithersburg, MD, USA.
Ching Ching
CC
Leow
Macrogenics, MacroGenics, Inc. , Rockville, MD, USA.
Gundo
G
Diedrich
MedImmune, LLC , Gaithersburg, MD, USA.
Melissa
M
Damschroder
MedImmune, LLC , Gaithersburg, MD, USA.
Ronald
R
Herbst
MedImmune, LLC , Gaithersburg, MD, USA.
Robert E
RE
Hollingsworth
MedImmune, LLC , Gaithersburg, MD, USA.
Kris F
KF
Sachsenmeier
Adenosine; CD73; MEDI9447; monoclonal antibody; syngeneic tumor model; tumor microenvironment