Novel genetically-humanized mouse model established to evaluate efficacy of therapeutic agents to human interleukin-6 receptor.

Abstract

For clinical trials of therapeutic monoclonal antibodies (mAbs) to be successful, their efficacy needs to be adequately evaluated in preclinical experiments. However, in many cases it is difficult to evaluate the candidate mAbs using animal disease models because of lower cross-reactivity to the orthologous target molecules. In this study we have established a novel humanized Castleman's disease mouse model, in which the endogenous interleukin-6 receptor gene is successfully replaced by human IL6R, and human IL6 is overexpressed. We have also demonstrated the therapeutic effects of an antibody that neutralizes human IL6R, tocilizumab, on the symptoms in this mouse model. Plasma levels of human soluble IL6R and human IL6 were elevated after 4-week treatment of tocilizumab in this mouse model similarly to the result previously reported in patients treated with tocilizumab. Our mouse model provides us with a novel means of evaluating the in vivo efficacy of human IL6R-specific therapeutic agents.

• Authors: Otoya Ueda, Hiromi Tateishi, Yoshinobu Higuchi, Etsuko Fujii, Atsuhiko Kato, Yosuke Kawase, Naoko A Wada, Takanori Tachibe, Mami Kakefuda, Chisato Goto, Makoto Kawaharada, Shin Shimaoka, Kunihiro Hattori, Kou-Ichi Jishage
• Journal: Scientific reports (Sci Rep) Vol. 3 Pg. 1196 ( 2013) ISSN: 2045-2322 [Electronic] England
• PMID: 23378927 (Publication Type: Evaluation Study, Journal Article)

Chemical References

• Antibodies, Monoclonal, Humanized
• Interleukin-6
• Receptors, Interleukin-6
• tocilizumab

Topics

• Animals
• Antibodies, Monoclonal, Humanized (immunology, therapeutic use)
• Castleman Disease (drug therapy, metabolism, pathology)
• Disease Models, Animal
• Female
• Gene Knock-In Techniques
• Humans
• Interleukin-6 (blood)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Receptors, Interleukin-6 (blood, genetics, metabolism)