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J. Biol. Chem., Vol. 279, Issue 17, 17875-17887, April 23, 2004
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Function-blocking Integrin 
v
6 Monoclonal Antibodies
DISTINCT LIGAND-MIMETIC AND NONLIGAND-MIMETIC CLASSES*
From the
Biogen Idec, Inc., Cambridge, Massachusetts 02142 and Lung Biology Center, Cardiovascular Research Institute, and Department of Medicine, University of California, San Francisco, California 94143
We have generated a panel of potent, selective monoclonal antibodies that bind human and mouse 
v
6 integrin with high affinity (up to 15 pM). A subset of these antibodies blocked the binding of v6 to the transforming growth factor-1 latency-associated peptide with IC50 values as low as 18 pM, and prevented the subsequent v6-mediated activation of transforming growth factor-1. The antibodies also inhibited v6 binding to fibronectin. The blocking antibodies form two biochemical classes. One class, exemplified by the ligand-mimetic antibody 6.8G6, bound to the integrin in a divalent cation-dependent manner, contained an RGD motif or a related sequence in CDR3 of the heavy chain, was blocked by RGD-containing peptides, and was internalized by v6-expressing cells. Despite containing an RGD sequence, 6.8G6 was specific for v6 and showed no cross-reactivity with the RGD-binding integrins v3, v8,or IIb3. The nonligand-mimetic blocking antibodies, exemplified by 6.3G9, were cation-independent, were not blocked by RGD-containing peptides, were not internalized, and did not contain RGD or related sequences. These two classes of antibody were unable to bind simultaneously to v6, suggesting that they may bind overlapping epitopes. The "ligand-mimetic" antibodies are the first to be described for v6 and resemble those described for IIb3. We also report for the first time the relative abilities of divalent cations to promote v6 binding to latency-associated peptide and to the ligand-mimetic antibodies. These antibodies should provide valuable tools to study the ligand-receptor interactions of v6 as well as the role of v6 in vivo.
Received for publication, November 4, 2003 , and in revised form, January 13, 2004.
* 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.
To whom correspondence should be addressed: Biogen Idec, Inc., 14 Cambridge Center, Cambridge, MA 02142. Tel.: 617-679-2351; Fax: 617-679-3148; E-mail: Paul.Weinreb{at}Biogenidec.com.
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