title: A novel therapeutic approach for thrombocytopenia by minibody agonist of the thrombopoietin receptor.
abstract: 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 biologic activities and appropriate serum half-life depending upon the disease indications. Here, we report that IgG antibodies against the thrombopoietin receptor (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 2 types of dysfunctional mutant Mpls that cause congenital amegakaryocytic thrombocytopenia (CAMT). This drastic conversion of biologic 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.
authors.affiliation: Chugai-Pharmaceutical Co., Ltd. Fuji-Gotemba Research Laboratory, Shizuoka, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Orita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsunoda
authors.forename: Naohiro
authors.initials: N
authors.lastname: Yabuta
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Nakano
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshino
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hirata
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ohtomo
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Nezu
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Sakumoto
authors.forename: Kouichiro
authors.initials: K
authors.lastname: Ono
authors.forename: Mikiyoshi
authors.initials: M
authors.lastname: Saito
authors.forename: Eiji
authors.initials: E
authors.lastname: Kumagai
authors.forename: Masahiko
authors.initials: M
authors.lastname: Nanami
authors.forename: Akihisa
authors.initials: A
authors.lastname: Kaneko
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshikubo
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsuchiya
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D001323:Autoantibodies / Q000276:immunology; D002352:Carrier Proteins / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D007114:Immunization; D007136:Immunoglobulins / Q000494:pharmacology*; D007947:Leukemia, Megakaryoblastic, Acute; D051379:Mice; D019463:Mice, Inbred MRL lpr; D015513:Oncogene Proteins / Q000819:agonists* / Q000276:immunology*; D018121:Receptors, Cytokine / Q000819:agonists* / Q000276:immunology*; D053628:Receptors, Thrombopoietin; D013921:Thrombocytopenia / Q000276:immunology* / Q000628:therapy*; D013926:Thrombopoietin / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D002352:Carrier Proteins; D007136:Immunoglobulins; C081296:Minibody (WT); C481270:Mpl protein, mouse; D015513:Oncogene Proteins; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D013926:Thrombopoietin