Chugai Seiyaku Kabushiki Kaisha

Other

Fuji Photo Film Company, Limited

Zenyth Operations Pty. Ltd.

Chugai Suyaku K.k.

Tetsuo Kojima

Tomoyuki Igawa

Atsushi Ohta

Tatsuya Kato

Kaori Kimura

Takashi Emura

Atsushi Matsuo

Hitoshi Iikura

Koji Takano

Tetsuhiro Soeda

Yusuke Yamagishi

Mikimasa Tanada

Naoaki Murao

Ryuichi Takeyama

Kousuke Asou

Shiori Kariyuki

Takeo Iida

Miki Kojima

Kazuhiko Nakano

Nozomi Hisada

Ryusuke Takano

Takuya Torizawa

Hiroyuki Tsunoda

Atsuhiko Maeda

Tatsuhiko Tachibana

Hirotake Shiraiwa

Takuya Shiraishi

Shinya Ishii

Zenjiro Sampei

Yoshinobu Higuchi

Mika Sakurai

Takehisa Kitazawa

Tsukasa Suzuki

Atsushi Muto

Taro Miyazaki

Kunihiro Hattori

Hiroyuki Saito

Chifumi Imai

Kazutaka Yoshihashi

Yukiko Nishida

Shigeo Hirano

Noriyuki Inoue

Andrew Donald Nash

Mitsuru Yamamoto

Douglas James Hilton

Nicos Anthony Nicola

Louis Jerry Fabri

Nozomi Yamaguchi

Tracy Ann Willson

Toshio Kitamura

Warren S Alexander

Masayoshi Oh-Eda

Yasufumi Kikuchi

Chiaki Senoo

Shota Tanaka

Jian-Guo Zhang

Alison Farley

Steven Rakar

Masatsugu Maeda

An object of the present invention is to provide methods of discovering drugs effective for tough targets, which have conventionally been discovered only with difficulty. The present invention relates to novel methods for cyclizing peptide compounds, and novel peptide compounds and libraries comprising the same, to achieve the above object.

Peptide-compound cyclization method

An objective of the present invention is to provide methods of synthesizing peptides containing structurally diverse amino acids using cell-free translation systems, which can accomplish excellent translational efficiency as compared to conventional techniques (the conventional techniques being methods which involve preparing aminoacyl-tRNAs which do not have protecting groups outside the translation systems without using ARS, and then adding the prepared aminoacyl-tRNAs into translation systems). In the present invention, it was found that amino acid-containing peptides can be synthesized efficiently by protecting an amino acid linked to tRNA with an appropriate protecting group, and then performing the step of deprotecting the protecting group of the amino acid linked to tRNA and the step of peptide translation from a template nucleic acid in a cell-free translation system in parallel.

Method for synthesizing peptides in cell-free translation system

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

Various bispecific antibodies that specifically bind to both blood coagulation factor IX/activated blood coagulation factor IX and blood coagulation factor X and functionally substitute for the cofactor function of blood coagulation factor VIII, that is, the function to promote activation of blood coagulation factor X by activated blood coagulation factor IX, were produced. From these antibodies, multispecific antigen-binding molecules having a high activity of functionally substituting for blood coagulation factor VIII were successfully discovered.

Methods of treatment that include the administration of bispecific antibodies

Bispecific antibodies

Focusing on the fact that antibody molecules with one H chain are not secreted when using the 'knobs-into-holes' method, the present inventors revealed that desired bispecific antibodies can be preferentially formed by first expressing the H and L chains of one arm, and then suppressing their expression, followed by expressing the H and L chains of the other arm so that first desired HL molecules (HaLa and HbLb) are constructed, and then the H chains are paired with each other (HL). The present invention was thus completed.

Process for producing antibodies

Antibody molecules that bind to IL-6 receptor

The present invention relates to methods of screening for commonly shared light chains, in which the method comprises the steps of (a) generating a host secreting the heavy chain of an antibody that binds to a desired antigen; (b) introducing an antibody light chain library into the host of step (a) to generate libraries presenting antibodies composed of the heavy chain and the light chains; (c) selecting a library presenting antibodies that bind specifically to the desired antigen of step (a); (d) introducing the library selected in step (c) into a host secreting the heavy chain of an antibody that binds to a desired antigen different from the antigen of step (a) to generate libraries that display antibodies composed of the heavy chains and light chains; and (e) selecting a library that displays antibodies that bind specifically to the desired antigen of step (d).

Methods of screening for antibody light chains

The present inventors succeeded in constructing bispecific antibodies, which bind to both the blood coagulation factor IX/activated blood coagulation factor IX and blood coagulation factor X, and functionally substitute for blood coagulation factor VIII/activated blood coagulation factor VIII which enhances the enzymatic reaction.

Bispecific antibody substituting for functional proteins

Bispecific diabody libraries can be constructed from scFv libraries efficiently and without troublesome procedures by a single treatment, placing restriction enzyme sites appropriately for antigen-encoding regions.

Methods for constructing scDb libraries

Cell strains with ligand-dependent (factor-dependent) proliferation are super-infected with antibody libraries against each of the various receptor chains. Antibody genes are recovered from strains that autonomously grow by the autocrine stimulation by agonistic antibodies formed by appropriate combinations, enabling effective screening of agonistic antibodies. In this method, effective screening can be carried out using antibodies as libraries. Furthermore, the manipulations are simple, and there is no need for complicated operations.

Methods of screening agonistic antibodies

The present invention relates generally to a novel haemopoietin receptor or derivatives thereof and to genetic sequences encoding same. Interaction between the novel receptor of the present invention and a cytokine ligand facilitates proliferation, differentiation and survival of a wide variety of cells. The novel receptor and its derivatives and the genetic sequences encoding same of the present invention are useful in the development of a wide range of agonists, antagonists, therapeutics and diagnostic reagents based on ligand interaction with its receptor.

Haemopoietin receptor and genetic sequence encoding same

The invention includes a DNA encoding a known translocatable protein, for example, human mpl, lacking secretory ability due to deletion of its secretory signal and the major part of the extracellular region thereof. This DNA is present in an expression vector into which a test cDNA from a cDNA library is ligated. The expression vector containing the known DNA and the test cDNA expresses a chimeric protein encoded by these two nucleic acid molecules. Cells expressing the newly constructed vector are capable of proliferating if the test cDNA is a secretory protein. Thus, cDNAs encoding secretory proteins including type I membrane proteins and type II membrane proteins can be detected and isolated by constructing a cDNA library and screening it for ability to promote cell proliferation.

Cellular assays for identifying signaling peptides

Growing community of inventors

Shizuoka, Japan

Tetsuo Kojima