Disrupting LILRB4/APOE Interaction by an Efficacious Humanized Antibody Reverses T-cell Suppression and Blocks AML Development

Xun Gui, Mi Deng, Hao Song, Yuanzhi Chen, Jingjing Xie, Zunling Li, Licai He, Fangfang Huang, Yixiang Xu, Yasuaki Anami, Hai Yu, Chenyi Yu, Leike Li, Zihao Yuan, Xiaoying Xu, Qihui Wang, Yan Chai, Tao Huang, Yi Shi, Kyoji TsuchikamaX. Charlene Liao, Ningshao Xia, George F. Gao, Ningyan Zhang, Cheng Cheng Zhang, Zhiqiang An

Research output: Contribution to journalArticle

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Abstract

Therapeutic strategies are urgently needed for patients with acute myeloid leukemia (AML). Leukocyte immunoglobulin-like receptor B4 (LILRB4), which suppresses T-cell activation and supports tissue infiltration of AML cells, represents an attractive drug target for anti-AML therapeutics. Here, we report the identification and development of an LILRB4-specific humanized mAb that blocks LILRB4 activation. This mAb, h128-3, showed potent activity in blocking the development of monocytic AML in various models including patient-derived xenograft mice and syngeneic immunocompetent AML mice. MAb h128-3 enhanced the anti-AML efficacy of chemotherapy treatment by stimulating mobilization of leukemia cells. Mechanistic studies revealed four concordant modes of action for the anti-AML activity of h128-3: (i) reversal of T-cell suppression, (ii) inhibition of monocytic AML cell tissue infiltration, (iii) antibody-dependent cellular cytotoxicity, and (iv) antibody-dependent cellular phagocytosis. Therefore, targeting LILRB4 with antibody represents an effective therapeutic strategy for treating monocytic AML.

Original languageEnglish (US)
Pages (from-to)1244-1257
Number of pages14
JournalCancer Immunology Research
Volume7
Issue number8
DOIs
StatePublished - Jan 1 2019

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Antibodies, Monoclonal, Humanized
Acute Myeloid Leukemia
Immunoglobulins
Leukocytes
T-Lymphocytes
Myeloid Cells
Antibodies
Phagocytosis
Heterografts
Leukemia
Therapeutics
Drug Therapy

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this

Disrupting LILRB4/APOE Interaction by an Efficacious Humanized Antibody Reverses T-cell Suppression and Blocks AML Development. / Gui, Xun; Deng, Mi; Song, Hao; Chen, Yuanzhi; Xie, Jingjing; Li, Zunling; He, Licai; Huang, Fangfang; Xu, Yixiang; Anami, Yasuaki; Yu, Hai; Yu, Chenyi; Li, Leike; Yuan, Zihao; Xu, Xiaoying; Wang, Qihui; Chai, Yan; Huang, Tao; Shi, Yi; Tsuchikama, Kyoji; Charlene Liao, X.; Xia, Ningshao; Gao, George F.; Zhang, Ningyan; Zhang, Cheng Cheng; An, Zhiqiang.

In: Cancer Immunology Research, Vol. 7, No. 8, 01.01.2019, p. 1244-1257.

Research output: Contribution to journalArticle

Gui, X, Deng, M, Song, H, Chen, Y, Xie, J, Li, Z, He, L, Huang, F, Xu, Y, Anami, Y, Yu, H, Yu, C, Li, L, Yuan, Z, Xu, X, Wang, Q, Chai, Y, Huang, T, Shi, Y, Tsuchikama, K, Charlene Liao, X, Xia, N, Gao, GF, Zhang, N, Zhang, CC & An, Z 2019, 'Disrupting LILRB4/APOE Interaction by an Efficacious Humanized Antibody Reverses T-cell Suppression and Blocks AML Development', Cancer Immunology Research, vol. 7, no. 8, pp. 1244-1257. https://doi.org/10.1158/2326-6066.CIR-19-0036
Gui, Xun ; Deng, Mi ; Song, Hao ; Chen, Yuanzhi ; Xie, Jingjing ; Li, Zunling ; He, Licai ; Huang, Fangfang ; Xu, Yixiang ; Anami, Yasuaki ; Yu, Hai ; Yu, Chenyi ; Li, Leike ; Yuan, Zihao ; Xu, Xiaoying ; Wang, Qihui ; Chai, Yan ; Huang, Tao ; Shi, Yi ; Tsuchikama, Kyoji ; Charlene Liao, X. ; Xia, Ningshao ; Gao, George F. ; Zhang, Ningyan ; Zhang, Cheng Cheng ; An, Zhiqiang. / Disrupting LILRB4/APOE Interaction by an Efficacious Humanized Antibody Reverses T-cell Suppression and Blocks AML Development. In: Cancer Immunology Research. 2019 ; Vol. 7, No. 8. pp. 1244-1257.
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abstract = "Therapeutic strategies are urgently needed for patients with acute myeloid leukemia (AML). Leukocyte immunoglobulin-like receptor B4 (LILRB4), which suppresses T-cell activation and supports tissue infiltration of AML cells, represents an attractive drug target for anti-AML therapeutics. Here, we report the identification and development of an LILRB4-specific humanized mAb that blocks LILRB4 activation. This mAb, h128-3, showed potent activity in blocking the development of monocytic AML in various models including patient-derived xenograft mice and syngeneic immunocompetent AML mice. MAb h128-3 enhanced the anti-AML efficacy of chemotherapy treatment by stimulating mobilization of leukemia cells. Mechanistic studies revealed four concordant modes of action for the anti-AML activity of h128-3: (i) reversal of T-cell suppression, (ii) inhibition of monocytic AML cell tissue infiltration, (iii) antibody-dependent cellular cytotoxicity, and (iv) antibody-dependent cellular phagocytosis. Therefore, targeting LILRB4 with antibody represents an effective therapeutic strategy for treating monocytic AML.",
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T1 - Disrupting LILRB4/APOE Interaction by an Efficacious Humanized Antibody Reverses T-cell Suppression and Blocks AML Development

AU - Gui, Xun

AU - Deng, Mi

AU - Song, Hao

AU - Chen, Yuanzhi

AU - Xie, Jingjing

AU - Li, Zunling

AU - He, Licai

AU - Huang, Fangfang

AU - Xu, Yixiang

AU - Anami, Yasuaki

AU - Yu, Hai

AU - Yu, Chenyi

AU - Li, Leike

AU - Yuan, Zihao

AU - Xu, Xiaoying

AU - Wang, Qihui

AU - Chai, Yan

AU - Huang, Tao

AU - Shi, Yi

AU - Tsuchikama, Kyoji

AU - Charlene Liao, X.

AU - Xia, Ningshao

AU - Gao, George F.

AU - Zhang, Ningyan

AU - Zhang, Cheng Cheng

AU - An, Zhiqiang

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Therapeutic strategies are urgently needed for patients with acute myeloid leukemia (AML). Leukocyte immunoglobulin-like receptor B4 (LILRB4), which suppresses T-cell activation and supports tissue infiltration of AML cells, represents an attractive drug target for anti-AML therapeutics. Here, we report the identification and development of an LILRB4-specific humanized mAb that blocks LILRB4 activation. This mAb, h128-3, showed potent activity in blocking the development of monocytic AML in various models including patient-derived xenograft mice and syngeneic immunocompetent AML mice. MAb h128-3 enhanced the anti-AML efficacy of chemotherapy treatment by stimulating mobilization of leukemia cells. Mechanistic studies revealed four concordant modes of action for the anti-AML activity of h128-3: (i) reversal of T-cell suppression, (ii) inhibition of monocytic AML cell tissue infiltration, (iii) antibody-dependent cellular cytotoxicity, and (iv) antibody-dependent cellular phagocytosis. Therefore, targeting LILRB4 with antibody represents an effective therapeutic strategy for treating monocytic AML.

AB - Therapeutic strategies are urgently needed for patients with acute myeloid leukemia (AML). Leukocyte immunoglobulin-like receptor B4 (LILRB4), which suppresses T-cell activation and supports tissue infiltration of AML cells, represents an attractive drug target for anti-AML therapeutics. Here, we report the identification and development of an LILRB4-specific humanized mAb that blocks LILRB4 activation. This mAb, h128-3, showed potent activity in blocking the development of monocytic AML in various models including patient-derived xenograft mice and syngeneic immunocompetent AML mice. MAb h128-3 enhanced the anti-AML efficacy of chemotherapy treatment by stimulating mobilization of leukemia cells. Mechanistic studies revealed four concordant modes of action for the anti-AML activity of h128-3: (i) reversal of T-cell suppression, (ii) inhibition of monocytic AML cell tissue infiltration, (iii) antibody-dependent cellular cytotoxicity, and (iv) antibody-dependent cellular phagocytosis. Therefore, targeting LILRB4 with antibody represents an effective therapeutic strategy for treating monocytic AML.

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