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Blood, 1 August 2001, Vol. 98, No. 3, pp. 652-660
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Epitope mapping of inhibitory antibodies against platelet
glycoprotein Ib reveals interaction between the leucine-rich
repeat N-terminal and C-terminal flanking domains of
glycoprotein Ib
Nancy Cauwenberghs,
Karen Vanhoorelbeke,
Stephan Vauterin,
Douwe F. Westra,
Gabriel Romo,
Eric G. Huizinga,
José A. Lopez,
Michael C. Berndt,
Jolàn Harsfalvi, and
Hans Deckmyn
From the Laboratory for Thrombosis Research, IRC, K U
Leuven Campus Kortrijk, Belgium; the Department of Haematology,
University Hospital Utrecht, The Netherlands; the Thrombosis Research
Section, Baylor College of Medicine, Houston, TX; the Baker Medical
Research Institute, Melbourne, Australia; and the Department of
Clinical Biochemistry and Molecular Pathology, University Medical
School, University of Debrecen, Hungary.
The interaction of von Willebrand factor (vWF) with the platelet
receptor glycoprotein Ib (GPIb) is important for platelet adhesion at high shear stress. Two functionally important antigenic areas within GPIb were identified through the characterization of 5 new inhibitory anti-GPIb monoclonal antibodies (mAbs). The binding
sites of 3 of these anti-GPIb mAbs, which were intercompeting and
potently inhibiting shear stress-induced binding of vWF, were mapped
within the N-terminal amino acid (aa) 1-59 area by the use of
canine-human chimeras. These antibodies, however, had little or no
effect (approximately 40% inhibition) on the binding of vWF induced by
either botrocetin or ristocetin. On the other hand, the anti-GPIb mAbs
24G10 and 6B4, which blocked GPIb-vWF binding under all conditions
examined, bound to 2 different regions of GPIb, aa 1-81 and aa
201-268, respectively. The epitope for 6B4 was further narrowed by
phage display revealing 2 sets of peptide sequences aligning within aa
259-262 and aa 230-242. In the latter region of GPIb, the
gain-of-function platelet-type von Willebrand disease (PT-vWD)
mutations have been identified. Alignment was partially confirmed
because the binding of 6B4 to recombinant GPIb fragments carrying
either one of the PT-vWD mutations was considerably impaired but not
completely abolished. In contrast, mAb 24G10 bound more strongly to
mutant PT-vWD GPIb. However, although 24G10 competed with 6B4 for
binding to platelets, it bound to an epitope within aa 1-81 of GPIb.
In conclusion, 2 functionally important areas within GPIb were
identified: one localized within the leucine-rich repeat N-terminal aa
1-59 area and one composed of residues aa 1-81 in close contact with aa 201-268. Moreover, further support is provided for the existence of an
intramolecular interaction between the N-terminal flanking (aa 1-81)
and C-terminal flanking (aa 201-268) regions.
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