Chugai Seiyaku Kabushiki Kaisha

Atsuhiko Maeda

Tomoyuki Igawa

Tatsuhiko Tachibana

Taichi Kuramochi

Shinya Ishii

Hirotake Shiraiwa

Kenta Haraya

Futa Mimoto

Takashi Nakai

Hiroyuki Tsunoda

Yuki Iwayanagi

Genki Nakamura

Masaru Muraoka

Shojiro Kadono

Tetsuo Kojima

Hitoshi Katada

Yuji Hori

Yoshinobu Higuchi

Mika Sakurai

Takeshi Baba

Junichi Nezu

Shigero Tamba

Yoshinori Watanabe

Masami Suzuki

Naoka Hironiwa

Atsushi Matsuo

Atsuhiko Kato

Yoshinao Ruike

Yasuko Kinoshita

Shun Shimizu

Takehisa Kitazawa

Hajime Miyamoto

Meiri Kawazoe

Akira Hayasaka

Keiko Esaki

Miho Funaki

Masakazu Fukuda

Shigero Tanba

Kiyoaki Sakata

Mika Endoh

Etsuko Takeiri

Eri Hashimoto

Machiko Fujino

The present inventors have discovered that in living organisms that have received an antigen-binding molecule containing an antigen-binding domain whose binding activity to an antigen changes depending on ion concentration conditions and containing an FcRn-binding domain having FcRn-binding activity in a neutral pH range, immune responses to the antigen are induced. Furthermore, the present inventors have discovered that in living organisms that have received an antigen-binding molecule containing an antigen-binding domain whose binding activity to an antigen changes depending on ion concentration conditions and containing an FcRn-binding domain having FcRn-binding activity in a neutral pH range, immune responses to the antigen are induced, and also the antigen-binding molecule has cytotoxicity or antiproliferative action against cancer cells, foreign biological species, or such that express the antigen to which the antigen-binding molecule binds.

Antigen-binding molecule inducing immune response to target antigen

Polypeptides with improved stability as compared to that of a parent polypeptide were successfully obtained by modifying at least one amino acid in a loop region of the antibody Fc region. Furthermore, by combining multiple amino acid modifications in the loop region, polypeptides with maintained or enhanced FcγR-binding activity as well as improved thermal stability, polypeptides with decreased FcγR-binding activity as well as improved thermal stability, and polypeptides with not only improved thermal stability and adjusted FcγR-binding activity but also decreased aggregate content, as compared to those of a parent polypeptide, were successfully obtained.

Modified Fc region of antibody

An objective of the present invention is to provide methods for promoting antigen uptake into cells by antigen-binding molecules, methods for increasing the number of times of antigen binding by one antigen-binding molecule, methods for promoting reduction of the antigen concentration in plasma by administering antigen-binding molecules, and methods for improving the plasma retention of an antigen-binding molecule, as well as antigen-binding molecules that allow enhanced antigen uptake into cells, antigen-binding molecules having an increased number of times of antigen binding, antigen-binding molecules that can promote reduction of the antigen concentration in plasma when administered, antigen-binding molecules with improved plasma retention, pharmaceutical compositions comprising the above antigen-binding molecules, and methods for producing them. The present inventors revealed that the above objective can be achieved by using antigen-binding molecules that show calcium-dependent antigen-antibody reaction.

Antigen-binding molecule capable of binding to plurality of antigen molecules repeatedly

The present inventors newly discovered that even if an antigen-binding molecule inhibits in vitro some of the physiological activities of an antigen having two or more physiological activities without inhibiting the remaining physiological activities, the molecule can promote elimination of the antigen from blood (from serum or plasma) and as a result reduce the physiological activities in vivo, when the antigen-binding molecule is conferred with the properties: (i) of binding to human FcRn under an acidic pH range condition; (ii) of binding under a neutral pH range condition to human Fc receptor stronger than native human IgG, and (iii) that its antigen-binding activity alters according to the ion concentration.

Methods for producing antibodies promoting disappearance of antigens having plurality of biological activities

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 antibodies having weaker antigen-binding activity at the early endosomal pH in comparison with that at the pH of plasma are capable of binding to multiple antigen molecules with a single antibody molecule, have long half-lives in plasma, and have improved durations of time in which they can bind to antigen.

Antigen-binding molecule capable of binding to two or more antigen molecules repeatedly

Antigen-binding molecule capable of binding two or more antigen molecules repeatedly

One nonexclusive aspect provides molecules further improved from antibodies that can bind to antigens in an ion concentration-dependent manner. An alternative nonexclusive aspect provides safe and more advantageous Fc region variants that have decreased binding to pre-existing ADA. An alternative nonexclusive aspect provides novel IL-8 antibodies that are superior as pharmaceuticals.

Methods of neutralizing IL-8 biological activity

The inventors discovered that viscosity of a protein solution can be estimated by measuring the apparent particle size or apparent molecular weight by a small angle X-ray scattering (SAXS) method or X-ray solution scattering method, which enables measurement of small amounts of samples, and then correlating those measurement results with viscosity of the protein solution.

Method for measuring viscosity of protein solution

The present invention provides pharmaceutical compositions comprising second-generation molecules that are superior than TOCILIZUMAB, by altering the amino acid sequences of the variable and constant regions of TOCILIZUMAB, which is a humanized anti-IL-6 receptor IgG1 antibody, to enhance the antigen-neutralizing ability and increase the pharmacokinetics, so that the therapeutic effect is exerted with a less frequency of administration, and the immunogenicity, safety and physicochemical properties (stability and homogeneity) are improved. The present invention also provides methods for producing these pharmaceutical compositions. The present inventors have successfully generated second-generation molecules that are superior to TOCILIZUMAB by appropriately combining amino acid sequence alterations in the CDR domains, variable regions, and constant regions.

Methods of reducing IL-6 activity for disease treatment

Nucleic acids encoding IL-8 antibodies

The present inventors carried out dedicated research to generate antibody constant regions with reduced Fc&#x3b3; receptor-binding activity by altering amino acid sequences in the antibody constant region. As a result, the present inventors successfully identified novel constant region sequences with reduced Fc&#x3b3; receptor-binding activity compared to conventional antibody constant regions.

Antibody constant region variants with reduced Fcgammar binding

Growing community of inventors

Shizuoka, Japan

Atsuhiko Maeda