Antibodies That Selectively Inhibit Leukocyte Function-associated Antigen 1 Binding to Intercellular Adhesion Molecule-3 Recognize a Unique Epitope within the CD11a I Domain (*)
- Minke E. Binnerts(1),
- Yvette van Kooyk(1)(§),
- Caroline P. Edwards(2),
- Mark Champe(2),
- Leonard Presta(2),
- Sarah C. Bodary(2),
- Carl G. Figdor(1) and
- Philip W. Berman(2)
- From the (1)Department of Tumor Immunology, University of Nijmegen, 6525 EX Nijmegen, The Netherlands and the
- (2)Department of Immunology, Genentech, Inc., South San Francisco, California 94080
- § To whom correspondence should be addressed: Dept. of Tumor Immunology, University Hospital Nijmegen St. Radboud, Philips van Leydenlaan 25, 6525 EX Nijmegen, The Netherlands. Tel.: 31-24-3617685; Fax: 31-24-3540339.
Abstract
Several studies indicate that the I domain located in the α chain (CD11a) of leukocyte function-associated antigen-1 (LFA-1;
CD11a/CD18) plays an essential role in ligand recognition. We recently identified three distinct epitopes (IdeA, IdeB, and
IdeC) within the CD11a I domain, recognized by antibodies that block binding of LFA-1 to intercellular adhesion molecules
(ICAM) 1, 2, and 3. In the present study, we used a series of human/murine CD11a I domain chimeras, to localize a fourth I
domain epitope (IdeD), recognized by three independently derived anti-CD11a antibodies that selectively block the binding
of LFA-1 to ICAM-3, but not to ICAM-1. The IdeD epitope depended on human CD11a residues Asp
and Ser
and was not present in CD11b or CD11c. Although mutation of Asp
and Ser
failed to abolish ICAM-3 adhesion of LFA-1 transfectants, alignment of these residues with the crystal structure of the CD11a
I domain suggested that the IdeD epitope is located in close proximity to residues (Ile
and Asn
) recently implicated in the ICAM-3 binding site(1). Interestingly, the IdeB and IdeC epitopes appeared to be in close proximity of a divalent cation binding pocket within
the CD11a I domain that regulates both ICAM-1 and ICAM-3 adhesion. Taken together, these data indicate that distinct regions
of the CD11a I domain contain epitopes for antibodies that either selectively inhibit binding of LFA-1 to ICAM-3, or interfere
with both ICAM-1 and ICAM-3 binding of LFA-1.
Footnotes
-
↵* This work was supported by Grant 900-509-185 from the Netherlands Organization for Scientific Research and Grant BGN 00.2318 from the Technology Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
-
↵1 The abbreviations used are:
- LFA-1 (CD11a/CD18)
-
leukocyte function-associated antigen 1
- ICAM
-
intercellular adhesion molecule
- mAb
-
monoclonal antibody
- H/M
-
human/murine
- MIDAS
-
metal ion-dependent adhesion site
- I domain
-
inserted domain.
-
↵2 M. E. Binnerts, Y. van Kooyk, and C. G. Figdor, unpublished observation.
-
↵3 M. E. Binnerts, Y. van Kooyk, and C. G. Figdor, manuscript in preparation.
-
- Received November 27, 1995.
- Revision received February 12, 1996.
