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Blood, 15 January 2005, Vol. 105, No. 2, pp. 562-566.
Prepublished online as a Blood First Edition Paper on September 16, 2004; DOI 10.1182/blood-2004-04-1482.
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Submitted April 23, 2004
Accepted August 7, 2004
A novel therapeutic approach for thrombocytopenia by minibody agonist of the thrombopoietin receptor
Tetsuro Orita, Hiroyuki Tsunoda, Naohiro Yabuta, Kiyotaka Nakano, Takeshi Yoshino, Yuichi Hirata, Toshihiko Ohtomo, Jun-ichi Nezu, Hirofumi Sakumoto, Kouichiro Ono, Mikiyoshi Saito, Eiji Kumagai, Masahiko Nanami, Akihisa Kaneko, Takashi Yoshikubo, and Masayuki Tsuchiya*
Fuji-Gotemba Research Labs, Chugai Pharmaceutical Co. Ltd., Shizuoka, Japan
* Corresponding author; email: tsuchiyamsy{at}chugai-pharm.co.jp.
Antibodies have brought valuable therapeutics in the clinical treatment of various diseases without serious adverse effects through their intrinsic features such as specific binding to the target antigen with high affinity, clinical safety as serum proteins, and long half-life. Agonist antibodies, furthermore, could be expected to maximize the value of therapeutic antibodies. Indeed several IgG/IgM antibodies have been reported to induce cellular growth/differentiation and apoptosis. These agonist antibodies, however, should be further improved to exert more potent biological activities, and appropriate serum half-life depending upon the disease indications. Here, we report that IgG antibodies against the thrombopoietin receptor (c-mpl, MPL), which have an absence or very weak agonist activity, can be engineered to be agonist minibodies, which include diabody or sc(Fv)2 as potent as natural ligand. Through this technological development, minibodies have been successfully constructed to bind and activate two types of dysfunctional mutant MPLs that cause congenital amegakaryocytic thrombocytopenia (CAMT). This drastic conversion of biological activities by designing minibodies can be widely applicable to generate agonist minibodies for clinical application, which will constitute a new paradigm in antibody-based therapeutics.
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