Chugai Seiyaku Kabushiki Kaisha

Nissan Chemical Industries Limited

Shojiro Kadono

Tomoyuki Igawa

Hitoshi Katada

Futa Mimoto

Taichi Kuramochi

Naoka Hironiwa

Shun Shimizu

Mika Sakurai

Kanako Tatsumi

Yuji Hori

Hiroki Kawauchi

Masaki Kamimura

Shigero Tamba

Takashi Emura

Atsuhiko Maeda

Tatsuhiko Tachibana

Hirotake Shiraiwa

Haruhiko Sato

Takuya Shiraishi

Masayuki Matsushita

Yuki Iwayanagi

Kenta Haraya

Meiri Kawazoe

Masami Hasegawa

Kazuhiro Ohara

Yoshiaki Watanabe

Atsushi Matsuo

Kazuhiko Ohrai

Masahiro Sakaitani

Yoshiyuki Suzuki

Takanori Shimizu

Masateru Ohta

Taro Miyazaki

Keishi Hayashi

Nobuya Ishii

Masataka Minami

Koji Toyama

Akira Hayasaka

Yoshinori Narita

Michiaki Adachi

Masayuki Haramura

Toshiro Kozono

Takaki Koga

Akihisa Sakamoto

Takeaki Kawai

Takayuki Kamikawa

Nasa Savory

Masakazu Sugiyama

The present inventors produced a heterodimerized polypeptide having an Fc region formed from two polypeptides with different amino acid sequences (a first polypeptide and a second polypeptide), and succeeded in producing a heterodimerized polypeptide containing an Fc region with improved Fc region function compared to that of a homodimer in which the Fc region is composed of only the first polypeptide or only the second polypeptide by conventional technology.

Heterodimerized polypeptide

It is intended to provide a method for efficiently and stably producing a heteromultimer by incubating homo variants of plural types of heavy chain constant region-containing polypeptides differing in antigen-binding activity under a reducing condition that reorganize the inter-polypeptide disulfide bond between cysteine residues outside of core hinge regions. A feature of the production method of the present invention is that amino acid residues in the core hinge regions do not form any disulfide bond.

Method for producing polypeptide hetero-oligomer

An objective of the present disclosure is to provide anti-CD137 antigen-binding molecules which have immunocyte-activating effect, cytotoxic activity, or anti-tumor activity, and meanwhile have reduced effect on non-tumor tissues such as normal tissues and produce less side effects, and methods of using the same. Anti-CD137 antigen-binding molecules which have immunocyte-activating effect, cytotoxic activity, or anti-tumor activity, and meanwhile have reduced effect on non-tumor tissues such as normal tissues and produce less side effects, are provided by discovering and producing CD137 antigen-binding molecules whose binding activity to CD137 depends on various substances (for example, small molecule compounds) in target tissues. Methods of using the same, pharmaceutical formulations, and such are also provided. The present disclosure also provides an antigen-binding molecule whose binding activity to an antigen varies depending on a small molecule compound, a preparation method thereof, and uses thereof.

Anti-CD137 antigen-binding molecule and utilization thereof

The present inventors have successfully prepared a library consisting essentially of a plurality of antigen-binding molecules differing in sequence from each other, the antigen-binding molecules each comprising an antibody variable region that has binding activity against a first antigen and a second antigen different from the first antigen, but does not bind to the first antigen and the second antigen at the same time. Use of the library of the present invention allows the obtainment of a variable region having enhanced ability to bind to the first antigen and the production of a bispecific antibody against the first antigen and a cancer antigen. Moreover, the present inventors have also successfully prepared an antigen-binding molecule comprising an antibody variable region that has binding activity against three different antigens, but does not bind to these antigens at the same time.

Library of antigen-binding molecules including modified antibody variable region

An objective of the present invention is to provide target tissue-specific antigen-binding molecules, antigen-binding molecules whose antigen-binding activity varies depending on the concentration of an unnatural compound, libraries comprising a plurality of the antigen-binding molecules which are different from one another, pharmaceutical compositions comprising the antigen-binding molecules, methods of screening for the antigen-binding molecules, and methods for producing the antigen-binding molecules. The present inventors created antigen-binding domains whose antigen-binding activity varies depending on the concentration of a small molecule compound or antigen-binding molecules containing an antigen-binding domain, and libraries comprising a plurality of the antigen-binding domains which are different from one another or antigen-binding domains, and demonstrated that the above-noted objective could be achieved by using the libraries. Various diseases originating from target tissues can be treated in a target tissue-specific manner by using the antigen-binding molecules of the present invention.

Antigen-binding molecules, the antigen-binding activity of which varies according to the concentration of compounds, and libraries of said molecules

The present inventors have successfully prepared an antigen-binding molecule comprising an antibody variable region that has binding activity against a molecule expressed on the surface of a T cell and a molecule expressed on the surface of any other immunocyte, but does not bind to these molecules at the same time. The present invention allows the preparation of an antigen-binding molecule capable of circumventing adverse reactions that may be caused by the cross-linking of T cells to other immunocytes, and provides an antigen-binding molecule suitable as a drug.

Antigen-binding molecule containing modified antibody variable region

The present invention demonstrated that the modification of the Fc region of an antigen-binding molecule into an Fc region that does not form in a neutral pH range a heterotetramer complex containing two molecules of FcRn and an active Fc&#x3b3; receptor improved the pharmacokinetics of the antigen-binding molecule and reduced the immune response to the antigen-binding molecule. The present invention also revealed methods for producing antigen-binding molecules having the properties described above, and successfully demonstrated that pharmaceutical compositions containing as an active ingredient such an antigen-binding molecule or an antigen-binding molecule produced by a production method of the present invention have excellent features over conventional antigen-binding molecules in that when administered, they exhibit improved pharmacokinetics and reduced in vivo immune response.

Method for altering plasma retention and immunogenicity of antigen-binding molecule

The present inventors discovered that problems of existing antibody pharmaceuticals can be solved by producing antigen-binding molecules that contain an antigen-binding domain whose antigen-binding activity varies depending on the concentration of a target tissue-specific compound. Use of antigen-binding molecules of the present invention enables various diseases that originate from a target tissue to be treated in a manner specific to the target tissue.

Target tissue-specific antigen-binding molecule

The present inventors have successfully prepared an antibody Fc region dimer that has binding activity against each of an antigen and Fc&#x3b3;R, but does not bind to the antigen and the Fc&#x3b3;R at the same time, and a polypeptide comprising the Fc region dimer. The present invention enables the preparation of a multispecific binding polypeptide capable of avoiding an adverse reaction that may be caused by its binding to an antigen and Fc&#x3b3;R at the same time. Thus, the present invention provides a polypeptide suitable as a drug.

Antigen-binding molecule containing modified Fc region

An objective of the present invention is to provide an Fc region variant with enhanced Fc&#x3b3;RIIb-binding activity, and/or enhanced binding selectivity to Fc&#x3b3;RIIb compared to Fc&#x3b3;RIIa (type R), as compared to those of a polypeptide containing an Fe region to which an amino acid alteration(s) has not been introduced; a polypeptide which includes the Fc region variant; a pharmaceutical composition containing the polypeptide; preventing therapeutic or preventive agent for immunological inflammatory diseases that includes the pharmaceutical composition; a production method thereof; and a method of enhancing Fc&#x3b3;RIIb-binding activity and also enhancing binding selectivity to Fc&#x3b3;RIIb compared to Fc&#x3b3;RIIa (type R). It was found that a polypeptide containing an antibody Fc region variant that contains an amino acid sequence in which an amino-acid alteration at position 238 (EU numbering) is combined with other specific amino-acid alterations enhances Fc&#x3b3;RIIb-binding activity, and/or enhances binding selectivity to Fc&#x3b3;RIIb compared to Fc&#x3b3;RIIa (type R).

FcgammaRIIB-specific Fc region variant

Growing community of inventors

Kanagawa, Japan

Shojiro Kadono