Kyowa Hakko Kirin Co., Limited

Masayuki Kai

Hideaki Yoshida

Shiro Kataoka

Kazuhiro Motoki

Tetsuya Hagiwara

This invention provides an agonist antibody to a human thrombopoietin receptor (human c-Mpl), and pharmaceutical compositions comprising the same for use in treatment of thrombocytopenia. The disclosed agonist antibody comprises (1) antibody constant regions comprising heavy and light chain constant regions, each of which may optionally contain domain substitutions, or may contain deletions, substitutions, additions, or insertions of amino acid residues, and (2) antibody variable regions capable of binding to and activating a human thrombopoietin receptor. The-agonist antibody further induces colony formation at a concentration of 10,000 ng/ml or lower, and has a maximal activity at least 50% higher than that of PEG-rHuMGDF and an 50% effective concentration (EC50) of 100 nM or less.

Agonist antibody to human thrombopoietin receptor

This invention provides an agonist antibody to a human thrombopoietin receptor (alias: human c-Mpl). More particularly, this invention provides an agonist antibody to a human thrombopoietin receptor, wherein the agonist antibody comprises: antibody constant regions comprising (1) amino acid sequences in a heavy chain constant region and a light chain constant region of a human antibody, (2) an amino acid sequence of a heavy chain constant region with a domain substituted between human antibody subclasses, and an amino acid sequence of a light chain constant region of a human antibody, or (3) amino acid sequences comprising a deletion(s), substitution(s), addition(s), or insertion(s) of one or several amino acid residues in the amino acid sequences of (1) or (2) above; and antibody variable regions capable of binding to and activating a human thrombopoietin receptor; and wherein the agonist antibody has the properties: (a) that the antibody induces colony formation at a concentration of 10,000 ng/ml or lower as determined by the CFU-MK colony formation assay using human umbilical-cord-blood-derived CD34+ cells; and (b) that the antibody has a maximal activity at least 50% higher than that of PEG-rHuMGDF and an 50% effective concentration (EC50) of 100 nM or less in the cell proliferation assay using UT7/TPO cell. Also provided is a pharmaceutical composition for treating thrombocytopenia comprising said antibody.

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Gunma, Japan

Masayuki Kai