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 language | English (US) |
|---|---|
| Article number | 02534 |
| Journal | Frontiers in Immunology |
| Volume | 9 |
| Issue number | NOV |
| DOIs | |
| State | Published - Nov 2 2018 |
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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 journal › Article
}
TY - JOUR
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
Y1 - 2018/11/2
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.
KW - Anti-drug antibodies (ADAs)
KW - Anti-mitochondrial antibodies (AMAs)
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)
UR - http://www.scopus.com/inward/record.url?scp=85056306155&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85056306155&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2018.02534
DO - 10.3389/fimmu.2018.02534
M3 - Article
C2 - 30450101
AN - SCOPUS:85056306155
VL - 9
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
IS - NOV
M1 - 02534
ER -