Making Better Antibodies Through Inhibition

Science Signaling  23 Aug 2011:
Vol. 4, Issue 187, pp. ec232
DOI: 10.1126/scisignal.4187ec232

Immunotherapies that promote antitumor immunity—including cancer vaccines, adoptive cellular therapies, and monoclonal antibodies—are increasingly being pursued in the clinic to treat a variety of cancers. One monoclonal antibody that is of particular interest is an agonist antibody specific for CD40, a member of the tumor necrosis family of receptors, which has shown modest efficacy in small clinical trials. Antibody ligation of CD40 promotes maturation of antigen-presenting cells, which in turn can drive enhanced T cell– and macrophage-mediated tumor toxicity. Li and Ravetch (see the Perspective by Smyth and Kershaw) now show that optimal antitumor immunity in a variety of mouse models required that the Fc portion of the CD40 antibody engaged the Fcγ receptor, FcγRIIB. This was unexpected because FcγRIIB typically transduces inhibitory signals to immune cells. Engineering of antibodies that preferentially bind activating Fcγ receptors showed that only the inhibitory Fcγ receptor was able to mediate an antitumor effect. Thus, careful engineering of the Fc region should be considered when designing monoclonal antibody therapeutics.

F. Li, J. V. Ravetch, Inhibitory Fcγ receptor engagement drives adjuvant and anti-tumor activities of agonistic CD40 antibodies. Science 333, 1030–1034 (2011). [Abstract] [Full Text]

M. J. Smyth, M. H. Kershaw, The adjuvant effects of antibodies. Science 333, 944–945 (2011). [Abstract] [Full Text]