Inhibition of CD73 AMP hydrolysis by a therapeutic antibody with a dual, non-competitive mechanism of action

• Published in: mAbs Vol. 8; no. 3; pp. 454 - 467
• Main Authors: Geoghegan, James C, Diedrich, Gundo, Lu, Xiaojun, Rosenthal, Kim, Sachsenmeier, Kris F, Wu, Herren, Dall'Acqua, William F, Damschroder, Melissa M
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 02.04.2016
• Subjects: 5'-Nucleotidase - antagonists & inhibitors; 5'-Nucleotidase - chemistry; Adenosine Monophosphate - chemistry; Antibodies, Monoclonal - chemistry; Antineoplastic Agents - chemistry; Enzyme Inhibitors - chemistry; GPI-Linked Proteins - antagonists & inhibitors; GPI-Linked Proteins - chemistry; Humans; Hydrolysis; CD73; hydrogen deuterium exchange; immuno-oncology; monoclonal antibody; epitope mapping
• ISSN: 1942-0862; 1942-0870
• DOI: 10.1080/19420862.2016.1143182

CD73 (ecto-5'-nucleotidase) has recently been established as a promising immuno-oncology target. Given its role in activating purinergic signaling pathways to elicit immune suppression, antagonizing CD73 (i.e., releasing the brake) offers a complimentary pathway to inducing anti-tumor immune responses. Here, we describe the mechanistic activity of a new clinical therapeutic, MEDI9447, a human monoclonal antibody that non-competitively inhibits CD73 activity. Epitope mapping, structural, and mechanistic studies revealed that MEDI9447 antagonizes CD73 through dual mechanisms of inter-CD73 dimer crosslinking and/or steric blocking that prevent CD73 from adopting a catalytically active conformation. To our knowledge, this is the first report of an antibody that inhibits an enzyme's function through 2 distinct modes of action. These results provide a finely mapped epitope that can be targeted for selective, potent, and non-competitive inhibition of CD73, as well as establish a strategy for inhibiting enzymes that function in both membrane-bound and soluble states.