Engineered antibody Fc variants with enhanced effector function

doi:10.1073/pnas.0508123103

Engineered antibody Fc variants with enhanced effector function

Xencor, Inc., 111 West Lemon Avenue, Monrovia, CA 91016

Edited by Pamela J. Bjorkman, California Institute of Technology, Pasadena, CA, and approved January 19, 2006
↵*G.A.L., W.D., S.K., and O.V. contributed equally to this work. (received for review September 16, 2005)

Abstract

Antibody-dependent cell-mediated cytotoxicity, a key effector function for the clinical efficacy of monoclonal antibodies, is mediated primarily through a set of closely related Fcγ receptors with both activating and inhibitory activities. By using computational design algorithms and high-throughput screening, we have engineered a series of Fc variants with optimized Fcγ receptor affinity and specificity. The designed variants display >2 orders of magnitude enhancement of in vitro effector function, enable efficacy against cells expressing low levels of target antigen, and result in increased cytotoxicity in an in vivo preclinical model. Our engineered Fc regions offer a means for improving the next generation of therapeutic antibodies and have the potential to broaden the diversity of antigens that can be targeted for antibody-based tumor therapy.

Footnotes

^†To whom correspondence should be addressed. E-mail: glazar{at}xencor.com
Author contributions: G.A.L., W.D., S.K., O.V., J.V., D.F.C., R.J.H., and B.I.D. designed research; W.D., S.K., O.V., J.S.P., L.H., C.C., H.S.C., A.E., S.C.Y., and J.V. performed research; G.A.L., W.D., S.K., O.V., J.V., D.F.C., R.J.H., and B.I.D. analyzed data; and G.A.L. wrote the paper.
Conflict of interest statement: G.A.L., W.D., S.K., O.V., J.S.P., L.H., C.C., H.S.C., A.E., S.C.Y., J.V., D.F.C., R.J.H., and B.I.D. are employees of Xencor. All commercial affiliations, financial interests, and patent-licensing arrangements that could be considered to pose a financial conflict of interest regarding the submitted article have been disclosed.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

ADCC,

Ab-dependent cell-mediated cytotoxicity;

ADCP,

Ab-dependent cell-mediated phagocytosis;

CDC,

complement-dependent cytotoxicity;

FcγR,

Fcγ receptor;

LDH,

lactate dehydrogenase;

NK,

natural killer;

PBMC,

peripheral blood mononuclear cell;

SPR,

surface plasmon resonance.
Freely available online through the PNAS open access option.