HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 33, 23514-23524, August 18, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/33/23514    most recent M604292200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dall'Acqua, W. F. Articles by Wu, H. Search for Related Content PubMed PubMed Citation Articles by Dall'Acqua, W. F. Articles by Wu, H. Social Bookmarking                      What's this?

Properties of Human IgG1s Engineered for Enhanced Binding to the Neonatal Fc Receptor (FcRn)^*

From the Department of Antibody Discovery and Protein Engineering, MedImmune, Inc., Gaithersburg, Maryland 20878

We describe here the functional implications of an increase in IgG binding to the neonatal Fc receptor. We have defined in a systematic fashion the relationship between enhanced FcRn binding of a humanized anti-respiratory sincytial virus (RSV) monoclonal antibody (MEDI-524) and the corresponding biological consequences in cynomolgus monkeys. The triple mutation M252Y/S254T/T256E (YTE) was introduced into the Fc portion of MEDI-524. Whereas these substitutions did not affect the ability of MEDI-524 to bind to its cognate antigen and inhibit RSV replication, they resulted in a 10-fold increase in its binding to both cynomolgus monkey and human FcRn at pH 6.0. MEDI-524-YTE was efficiently released from FcRn at pH 7.4 in both cases. We show that MEDI-524-YTE consistently exhibited a nearly 4-fold increase in serum half-life in cynomolgus monkeys when compared with MEDI-524. This constituted the largest half-life improvement described to date for an IgG in a primate. For the first time, we demonstrate that these sustained serum levels resulted in an up to 4-fold increase in lung bioavailability. Importantly, we also establish that our non-human primate model is relevant to human. Finally, we report that the YTE triple substitution provided a means to modulate the antibody-dependent cell-mediated cytotoxicity (ADCC) activity of a humanized IgG1 directed against the human integrin _v3. Therefore, the YTE substitutions allow the simultaneous modulation of serum half-life, tissue distribution and activity of a given human IgG1.

Received for publication, May 4, 2006 , and in revised form, June 13, 2006.

^* 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 may be addressed. Tel.: 301-398-4536; Fax: 301-398-9536; E-mail: dall'acquaw{at}medimmune.com. ²To whom correspondence may be addressed. Tel.: 301-398-4640; Fax: 301-398-9640; E-mail: wuh{at}medimmune.com.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				Y. A. Yeung, M. K. Leabman, J. S. Marvin, J. Qiu, C. W. Adams, S. Lien, M. A. Starovasnik, and H. B. Lowman Engineering Human IgG1 Affinity to Human Neonatal Fc Receptor: Impact of Affinity Improvement on Pharmacokinetics in Primates J. Immunol., June 15, 2009; 182(12): 7663 - 7671. [Abstract] [Full Text] [PDF]

				M. Sack, A. Paetz, R. Kunert, M. Bomble, F. Hesse, G. Stiegler, R. Fischer, H. Katinger, E. Stoeger, and T. Rademacher Functional analysis of the broadly neutralizing human anti-HIV-1 antibody 2F5 produced in transgenic BY-2 suspension cultures FASEB J, June 1, 2007; 21(8): 1655 - 1664. [Abstract] [Full Text] [PDF]

				A. Datta-Mannan, D. R. Witcher, Y. Tang, J. Watkins, and V. J. Wroblewski Monoclonal Antibody Clearance: IMPACT OF MODULATING THE INTERACTION OF IgG WITH THE NEONATAL Fc RECEPTOR J. Biol. Chem., January 19, 2007; 282(3): 1709 - 1717. [Abstract] [Full Text] [PDF]