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 Tsuchikama; X. Charlene Liao; Ningshao Xia; George F. Gao; Ningyan Zhang; Cheng Cheng Zhang; Zhiqiang An

doi:10.1158/2326-6066.CIR-19-0036

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 journal › Article › peer-review

37 Scopus citations

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 language	English (US)
Pages (from-to)	1244-1257
Number of pages	14
Journal	Cancer Immunology Research
Volume	7
Issue number	8
DOIs	https://doi.org/10.1158/2326-6066.CIR-19-0036
State	Published - 2019

ASJC Scopus subject areas

Immunology
Cancer Research

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10.1158/2326-6066.CIR-19-0036

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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., ... An, Z. (2019). Disrupting LILRB4/APOE Interaction by an Efficacious Humanized Antibody Reverses T-cell Suppression and Blocks AML Development. Cancer Immunology Research, 7(8), 1244-1257. https://doi.org/10.1158/2326-6066.CIR-19-0036

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

@article{8e75b4d473f54ced9e467eead49c477a,

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

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.",

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

note = "Funding Information: We are very grateful to Dr. Xuejun Fan, Dr. Wei Xiong, and Ms. Hui Deng for the technical assistance and helpful advice. We thank Dr. Georgina T. Salazar for editing the manuscript. This work was supported by the Cancer Prevention and Research Institute of Texas (RP140402, DP150056, RP180435, and RP150551), the Welch Foundation (AU-0042-20030616 and I-1834), and the National Cancer Institute (1R01CA172268). Publisher Copyright: {\textcopyright} 2019 American Association for Cancer Research.",

year = "2019",

doi = "10.1158/2326-6066.CIR-19-0036",

language = "English (US)",

volume = "7",

pages = "1244--1257",

journal = "Cancer Immunology Research",

issn = "2326-6066",

publisher = "American Association for Cancer Research Inc.",

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TY - JOUR

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

N1 - Funding Information: We are very grateful to Dr. Xuejun Fan, Dr. Wei Xiong, and Ms. Hui Deng for the technical assistance and helpful advice. We thank Dr. Georgina T. Salazar for editing the manuscript. This work was supported by the Cancer Prevention and Research Institute of Texas (RP140402, DP150056, RP180435, and RP150551), the Welch Foundation (AU-0042-20030616 and I-1834), and the National Cancer Institute (1R01CA172268). Publisher Copyright: © 2019 American Association for Cancer Research.

PY - 2019

Y1 - 2019

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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UR - http://www.scopus.com/inward/citedby.url?scp=85070515052&partnerID=8YFLogxK

U2 - 10.1158/2326-6066.CIR-19-0036

DO - 10.1158/2326-6066.CIR-19-0036

M3 - Article

C2 - 31213474

AN - SCOPUS:85070515052

SN - 2326-6066

VL - 7

SP - 1244

EP - 1257

JO - Cancer Immunology Research

JF - Cancer Immunology Research

IS - 8

ER -

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

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