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Originally published In Press as doi:10.1074/jbc.M510171200 on December 5, 2005

J. Biol. Chem., Vol. 281, Issue 8, 5032-5036, February 24, 2006
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The Carbohydrate at Fc{gamma}RIIIa Asn-162

AN ELEMENT REQUIRED FOR HIGH AFFINITY BINDING TO NON-FUCOSYLATED IgG GLYCOFORMS*

Claudia Ferrara{ddagger}§, Fiona Stuart{ddagger}, Peter Sondermann{ddagger}, Peter Brünker{ddagger}, and Pablo Umaña{ddagger}1

From the {ddagger}GLYCART Biotechnology AG (Roche Group), Wagistrasse 18, CH-8952 Schlieren, Switzerland and the §Institute of Biotechnology, ETH Zürich, CH-8093 Zürich, Switzerland

Fc{gamma}RIIIa plays a prominent role in the elimination of tumor cells by antibody-based cancer therapies. Non-fucosylated bisected IgGs bind this receptor with increased affinity and trigger Fc{gamma}RIII-mediated effector functions more efficiently than native, fucosylated antibodies. In this study the contribution of the carbohydrates of both binding partners to the strength of the complex was analyzed. Glycoengineering of the antibody increased affinity for two polymorphic forms of soluble human Fc{gamma}RIIIa (by up to 50-fold) but did not affect binding to the inhibitory Fc{gamma}RIIb receptor. While the absence of carbohydrate at Fc{gamma}RIIIa's Asn-162 increased affinity for native IgG, presumably due to the removal of steric hindrance caused by the bulky sugars, it unexpectedly reduced affinity for glycoengineered (GE) antibodies by over one order of magnitude, bringing the affinity down to the same level as for native IgG. We conclude that the high affinity between GE antibodies and Fc{gamma}RIII is mediated by productive interactions formed between the receptor carbohydrate attached at Asn-162 and regions of the Fc that are only accessible when it is nonfucosylated. As Fc{gamma}RIIIa and Fc{gamma}RIIIb are the only human Fc{gamma} receptors glycosylated at this position, the proposed interactions explain the observed selective affinity increase of GE antibodies for only these receptors. Furthermore, we predict from our structural model that only one of the two Fc-fucose residues needs to be absent for increased binding affinity toward Fc{gamma}RIII. This information can be exploited for the design of new antibodies with altered Fc receptor binding affinity and enhanced therapeutic potential.

Received for publication, September 15, 2005 , and in revised form, December 2, 2005.

* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom correspondence should be addressed. Tel.: 41-44-755-6161; Fax: 41-44-755-61-60; E-mail: pablo.umana{at}roche.com.


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