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ID 114467
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Anti-hCD20 Antibody Ameliorates Murine PBC
Moritoki, Yuki Akita University|University of Hawaii
Nakamura, Yuka Akita University
Kikuchi, Kentaro Teikyo University
Shiota, Akira Institute of Immunology
Ohsugi, Yoshiyuki Ohsugi BioPharma Consulting
Lian, Zhe-Xiong South China University of Technology
Zhang, Weici University of California
Yang, Guo-Xiang University of California
Ueki, Shigeharu Akita University
Takeda, Masahide Akita University
Omokawa, Ayumi Akita University
Saga, Tomoo Akita University
Saga, Akiko Akita University
Watanabe, Daisuke Watanabe Internal Medicine Clinic
Miura, Masahito Omagari Kosei Medical Center
Ueno, Yoshiyuki Yamagata University
Leung, Patrick S. C. University of California
Tanaka, Atsushi Teikyo University
Gershwin, M. Eric University of California
Hirokawa, Makoto Akita University
anti-drug antibodies (ADAs)
anti-mitochondrial antibodies (AMAs)
B cell depletion therapy
human anti-chimeric antibodies (HACAs)
humanized anti-human CD20 antibody
mouse anti-human antibodies (MAHAs)
primary biliary cholangitis (PBC)
Content Type
Journal Article
There is considerable interest in expanding B cell-targeted therapies in human autoimmune diseases. However, clinical trials in human primary biliary cholangitis (PBC) using a chimeric antibody against human CD20 (hCD20) have showed limited efficacy. Two potential explanations for these disappointing results are the appearance of anti-drug antibodies (ADAs) and the high frequency of patients with moderate PBC or patients who had failed ursodeoxycholic acid treatment. Here, we studied a novel humanized IgG1 antibody against hCD20 and explored its efficacy in early stage PBC using a well-defined murine model. We developed a unique murine model consisting of dnTGF-bRII mice expressing hCD20 and human Fcg receptors (hFcγRs). Beginning at 4–6 weeks of age, equivalent to stage I/II human PBC, female mice were given weekly injections of an anti-hCD20 antibody (TKM-011) or vehicle control, and monitored for liver histology as well as a broad panel of immunological readouts. After 16 weeks’ treatment, we observed a significant reduction in portal inflammation, a decrease in liver-infiltrating mononuclear cells as well as a reduction in liver CD8+ T cells. Importantly, direct correlations between numbers of liver non-B cells and B cells (r = 0.7426, p = 0.0006) and between numbers of liver memory CD8+ T cells and B cells (r = 0.6423, p = 0.0054) were apparent. Accompanying these changes was a dramatic reduction in anti-mitochondrial antibodies (AMAs), interleukin (IL)-12p40 and IL-5, and elevated levels of the anti-inflammatory chemokine CXCL1/KC. In mice that developed ADAs, clinical improvements were less pronounced. Sustained treatment with B cell-targeted therapies may broadly inhibit effector pathways in PBC, but may need to be administered early in the natural history of PBC.
Journal Title
Frontiers in Immunology
Frontiers Media S.A.
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Copyright © 2018 Moritoki, Tsuneyama, Nakamura, Kikuchi, Shiota, Ohsugi, Lian, Zhang, Yang, Ueki, Takeda, Omokawa, Saga, Saga,Watanabe, Miura, Ueno, Leung, Tanaka, Gershwin andHirokawa. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). ( The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
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Medical Sciences