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A novel antiplatelet antibody therapy that induces cAMP-dependent endocytosis of the GPVI/Fc receptor γ-chain complex
Hiroshi Takayama, … , Michiru Kurihara, Shoji Furusako
Hiroshi Takayama, … , Michiru Kurihara, Shoji Furusako
Published April 1, 2008
Citation Information: J Clin Invest. 2008;118(5):1785-1795. https://doi.org/10.1172/JCI32513.
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Research Article Hematology Article has an altmetric score of 3

A novel antiplatelet antibody therapy that induces cAMP-dependent endocytosis of the GPVI/Fc receptor γ-chain complex

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Abstract

Platelet adhesion to vascular subendothelium, mediated in part by interactions between collagen and glycoprotein VI (GPVI) complexed with Fc receptor γ-chain, is crucial for thrombus formation. Antiplatelet therapy benefits patients with various thrombotic and ischemic diseases, but the safety and efficacy of existing treatments are limited. Recent data suggest GPVI as a promising target for a novel antiplatelet therapy, for example, GPVI-specific Abs that deplete GPVI from the surface of platelets. Here, we characterized GPVI-specific auto-Abs (YA-Abs) from the first reported patient with ongoing platelet GPVI deficiency caused by the YA-Abs. To obtain experimentally useful human GPVI–specific mAbs with characteristics similar to YA-Abs, we generated human GPVI–specific mouse mAbs and selected 2 representative mAbs, mF1201 and mF1232, whose binding to GPVI was inhibited by YA-Abs. In vitro, mF1201, but not mF1232, induced human platelet activation and GPVI shedding, and mF1232 inhibited collagen-induced human platelet aggregation. Administration of mF1201 and mF1232 to monkeys caused GPVI immunodepletion with and without both significant thrombocytopenia and GPVI shedding, respectively. When a human/mouse chimeric form of mF1232 (cF1232) was labeled with a fluorescent endocytosis probe and administered to monkeys, fluorescence increased in circulating platelets and surface GPVI was lost. Loss of platelet surface GPVI mediated by cF1232 was successfully reproduced in vitro in the presence of a cAMP-elevating agent. Thus, we have characterized cAMP-dependent endocytosis of GPVI mediated by a human GPVI–specific mAb as what we believe to be a novel antiplatelet therapy.

Authors

Hiroshi Takayama, Yoshitaka Hosaka, Kazuyuki Nakayama, Kamon Shirakawa, Katsuki Naitoh, Tomokazu Matsusue, Mikihiko Shinozaki, Motoyasu Honda, Yukiko Yatagai, Tetsushi Kawahara, Jiro Hirose, Tooru Yokoyama, Michiru Kurihara, Shoji Furusako

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Figure 4

Effects of mF1232 or mF1201 injected into cynomolgus monkeys on GPVI immunodepletion, collagen-induced platelet aggregation, and platelet counts.

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Effects of mF1232 or mF1201 injected into cynomolgus monkeys on GPVI imm...
mF1232 (white bars) or mF1201 (black bars) was i.v. injected at a dose of 0.3 mg/kg into monkeys. Blood was collected on day 0 (0d), day 1 (1d), and day 2 (2d) after injection. The level of GPVI, FcRγ, and GPIIIa in platelet lysates (A) and the expression of surface GPVI (B) were analyzed by western blotting and by flow cytometry, respectively, using each specific Ab. (A) Representative data of western blotting from 3 separate experiments are shown at the top of the panel. The band density of GPVI (middle panel) or FcRγ (bottom panel) was quantified by a Typhoon Scanner 9410 and shown as percentage of that on day 0. (B) Mean fluorescence intensity was normalized to 100 for that on day 0. Maximal platelet aggregation was monitored using PRP stimulated with 2 μg/ml collagen (C), and platelet (PLT) counts in whole blood (D) were determined. Data are presented as mean ± SEM of 3 separate experiments. *P < 0.05, **P < 0.01 versus day 0.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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