Anti-drug antibodies against a novel humanized anti-CD20 antibody impair its therapeutic effect on primary biliary cholangitis in human CD20- and FcγR-expressing mice

Yuki Moritoki, Koichi Tsuneyama, Yuka Nakamura, Kentaro Kikuchi, Akira Shiota, Yoshiyuki Ohsugi, Zhe Xiong Lian, Weici Zhang, Guo Xiang Yang, Shigeharu Ueki, Masahide Takeda, Ayumi Omokawa, Tomoo Saga, Akiko Saga, Daisuke Watanabe, Masahito Miura, Yoshiyuki Ueno, Patrick S Leung, Atsushi Tanaka, M. Eric GershwinMakoto Hirokawa

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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-βRII mice expressing hCD20 and human Fcγ 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.

Original languageEnglish (US)
Article number02534
JournalFrontiers in Immunology
Volume9
Issue numberNOV
DOIs
StatePublished - Nov 2 2018

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Antibodies, Monoclonal, Humanized
Cholangitis
Therapeutic Uses
Anti-Idiotypic Antibodies
Pharmaceutical Preparations
B-Lymphocytes
Liver
Cell- and Tissue-Based Therapy
Chemokine CXCL1
T-Lymphocytes
Ursodeoxycholic Acid
Fc Receptors
Antibodies
Interleukins
Interleukin-5
Natural History
Autoimmune Diseases
Histology
Anti-Inflammatory Agents
Therapeutics

Keywords

  • 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)

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Anti-drug antibodies against a novel humanized anti-CD20 antibody impair its therapeutic effect on primary biliary cholangitis in human CD20- and FcγR-expressing mice. / Moritoki, Yuki; Tsuneyama, Koichi; Nakamura, Yuka; Kikuchi, Kentaro; Shiota, Akira; Ohsugi, Yoshiyuki; Lian, Zhe Xiong; Zhang, Weici; Yang, Guo Xiang; Ueki, Shigeharu; Takeda, Masahide; Omokawa, Ayumi; Saga, Tomoo; Saga, Akiko; Watanabe, Daisuke; Miura, Masahito; Ueno, Yoshiyuki; Leung, Patrick S; Tanaka, Atsushi; Gershwin, M. Eric; Hirokawa, Makoto.

In: Frontiers in Immunology, Vol. 9, No. NOV, 02534, 02.11.2018.

Research output: Contribution to journalArticle

Moritoki, Y, Tsuneyama, K, Nakamura, Y, Kikuchi, K, Shiota, A, Ohsugi, Y, Lian, ZX, Zhang, W, Yang, GX, Ueki, S, Takeda, M, Omokawa, A, Saga, T, Saga, A, Watanabe, D, Miura, M, Ueno, Y, Leung, PS, Tanaka, A, Gershwin, ME & Hirokawa, M 2018, 'Anti-drug antibodies against a novel humanized anti-CD20 antibody impair its therapeutic effect on primary biliary cholangitis in human CD20- and FcγR-expressing mice', Frontiers in Immunology, vol. 9, no. NOV, 02534. https://doi.org/10.3389/fimmu.2018.02534
Moritoki, Yuki ; Tsuneyama, Koichi ; Nakamura, Yuka ; Kikuchi, Kentaro ; Shiota, Akira ; Ohsugi, Yoshiyuki ; Lian, Zhe Xiong ; Zhang, Weici ; Yang, Guo Xiang ; Ueki, Shigeharu ; Takeda, Masahide ; Omokawa, Ayumi ; Saga, Tomoo ; Saga, Akiko ; Watanabe, Daisuke ; Miura, Masahito ; Ueno, Yoshiyuki ; Leung, Patrick S ; Tanaka, Atsushi ; Gershwin, M. Eric ; Hirokawa, Makoto. / Anti-drug antibodies against a novel humanized anti-CD20 antibody impair its therapeutic effect on primary biliary cholangitis in human CD20- and FcγR-expressing mice. In: Frontiers in Immunology. 2018 ; Vol. 9, No. NOV.
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T1 - Anti-drug antibodies against a novel humanized anti-CD20 antibody impair its therapeutic effect on primary biliary cholangitis in human CD20- and FcγR-expressing mice

AU - Moritoki, Yuki

AU - Tsuneyama, Koichi

AU - Nakamura, Yuka

AU - Kikuchi, Kentaro

AU - Shiota, Akira

AU - Ohsugi, Yoshiyuki

AU - Lian, Zhe Xiong

AU - Zhang, Weici

AU - Yang, Guo Xiang

AU - Ueki, Shigeharu

AU - Takeda, Masahide

AU - Omokawa, Ayumi

AU - Saga, Tomoo

AU - Saga, Akiko

AU - Watanabe, Daisuke

AU - Miura, Masahito

AU - Ueno, Yoshiyuki

AU - Leung, Patrick S

AU - Tanaka, Atsushi

AU - Gershwin, M. Eric

AU - Hirokawa, Makoto

PY - 2018/11/2

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N2 - 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-βRII mice expressing hCD20 and human Fcγ 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.

AB - 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-βRII mice expressing hCD20 and human Fcγ 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.

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KW - B cell depletion therapy

KW - Human anti-chimeric antibodies (HACAs)

KW - Humanized anti-human CD20 antibody

KW - Mouse anti-human antibodies (MAHAs)

KW - Primary biliary cholangitis (PBC)

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