Inhibition of CD73 AMP hydrolysis by a therapeutic antibody with a dual, non-competitive mechanism of action.
MAbs
; 8(3): 454-67, 2016.
Article
em En
| MEDLINE
| ID: mdl-26854859
ABSTRACT
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.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
5'-Nucleotidase
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Monofosfato de Adenosina
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Inibidores Enzimáticos
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Anticorpos Monoclonais
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Antineoplásicos
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article