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

被引：66

作者：

Gui, Xun ^{[1
]}

Deng, Mi ^{[2
]}

Song, Hao ^{[3
]}

Chen, Yuanzhi ^{[1
,4
]}

Xie, Jingjing ^{[2
,5
]}

Li, Zunling ^{[2
,5
]}

He, Licai ^{[2
,6
]}

Huang, Fangfang ^{[2
,7
]}

Xu, Yixiang ^{[1
]}

Anami, Yasuaki ^{[1
]}

Yu, Hai ^{[4
]}

Yu, Chenyi ^{[1
,8
]}

Li, Leike ^{[1
]}

Yuan, Zihao ^{[1
]}

Xu, Xiaoying ^{[9
]}

Wang, Qihui ^{[1
,9
]}

Chai, Yan ^{[9
]}

Huang, Tao ^{[10
]}

Shi, Yi ^{[9
]}

Tsuchikama, Kyoji ^{[1
]}

Liao, X. Charlene ^{[10
]}

Xia, Ningshao ^{[4
]}

Gao, George F. ^{[9
,11
]}

Zhang, Ningyan ^{[1
]}

Zhang, Cheng Cheng ^{[2
]}

An, Zhiqiang ^{[1
]}

机构：

[1] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Brown Fdn, Texas Therapeut Inst, Houston, TX 77030 USA

[2] Univ Texas Southwestern Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA

[3] Chinese Acad Sci, Beijing Inst Life Sci, RNIH, Beijing, Peoples R China

[4] Xiamen Univ, Sch Publ Hlth, Xiamen, Fujian, Peoples R China

[5] Binzhou Med Univ, Basic Med Sch, Taishan Immunol Program, Yantai, Peoples R China

[6] Wenzhou Med Univ, Sch Lab Med & Life Sci, Key Lab Lab Med, Minist Educ, Wenzhou, Peoples R China

[7] Xiamen Univ, Zhongshan Hosp, Dept Hematol, Xiamen, Fujian, Peoples R China

[8] Cent South Univ, Sch Xiangya Med, Changsha, Hunan, Peoples R China

[9] Chinese Acad Sci, Inst Microbiol, CAS Key Lab Microbial Physiol & Metab Engn, Beijing, Peoples R China

[10] Immune Onc Therapeut Inc, Palo Alto, CA USA

[11] Chinese Ctr Dis Control & Prevent China CDC, Natl Inst Viral Dis Control & Prevent, Beijing, Peoples R China

来源：

CANCER IMMUNOLOGY RESEARCH | 2019年 / 7卷 / 08期

关键词：

ACUTE MYELOID-LEUKEMIA; MONOCLONAL-ANTIBODIES; IN-VIVO; RECEPTOR; INNATE; EXPRESSION; GENERATION; INHIBITOR; THERAPY; DEPENDS;

D O I：

10.1158/2326-6066.CIR-19-0036

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Therapeutic strategies are urgently needed for patients with acute myeloid leukemia (AML). Leukocyte immunoglobulinlike 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 immunocom-petent 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) antibodydependent cellular phagocytosis. Therefore, targeting LILRB4 with antibody represents an effective therapeutic strategy for treating monocytic AML.

引用

页码：1244 / 1257

页数：14

共 38 条

[1] High-Throughput Epitope Binning Assays on Label-Free Array-Based Biosensors Can Yield Exquisite Epitope Discrimination That Facilitates the Selection of Monoclonal Antibodies with Functional Activity [J].

Abdiche, Yasmina Noubia ;

Miles, Adam ;

Eckman, Josh ;

Foletti, Davide ;

Van Blarcom, Thomas J. ;

Yeung, Yik Andy ;

Pons, Jaume ;

Rajpal, Arvind .

PLOS ONE, 2014, 9 (03)

[2] HLA-G: An Immune Checkpoint Molecule [J].

Carosella, Edgardo D. ;

Rouas-Freiss, Nathalie ;

Roux, Diana Tronik-Le ;

Moreau, Philippe ;

LeMaoult, Joel .

ADVANCES IN IMMUNOLOGY, VOL 127, 2015, 127 :33-144

[3] Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia [J].

Chen, Zhengshan ;

Shojaee, Seyedmehdi ;

Buchner, Maike ;

Geng, Huimin ;

Lee, JaeWoong ;

Klemm, Lars ;

Titz, Boern ;

Graeber, Thomas G. ;

Park, Eugene ;

Tan, Ying Xim ;

Satterthwaite, Anne ;

Paietta, Elisabeth ;

Hunger, Stephen P. ;

Willman, Cheryl L. ;

Melnick, Ari ;

Loh, Mignon L. ;

Jung, Jae U. ;

Coligan, John E. ;

Bolland, Silvia ;

Mak, Tak W. ;

Limnander, Andre ;

Jumaa, Hassan ;

Reth, Michael ;

Weiss, Arthur ;

Lowell, Clifford A. ;

Mueschen, Markus .

NATURE, 2015, 521 (7552) :357-+

[4] Crystal Structure of Leukocyte Ig-like Receptor LILRB4 (ILT3/LIR-5/CD85k) A MYELOID INHIBITORY RECEPTOR INVOLVED IN IMMUNE TOLERANCE [J].

Cheng, Hao ;

Mohammed, Fiyaz ;

Nam, Gol ;

Chen, Yong ;

Qi, Jianxun ;

Garner, Lee I. ;

Allen, Rachel L. ;

Yan, Jinghua ;

Willcox, Benjamin E. ;

Gao, George F. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (20) :18013-18025

[5] Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets [J].

Clynes, RA ;

Towers, TL ;

Presta, LG ;

Ravetch, JV .

NATURE MEDICINE, 2000, 6 (04) :443-446

[6] Cancer Immunotherapy [J].

Couzin-Frankel, Jennifer .

SCIENCE, 2013, 342 (6165) :1432-1433

[7] Mechanisms of Immune Tolerance in Leukemia and Lymphoma [J].

Curran, Emily K. ;

Godfrey, James ;

Kline, Justin .

TRENDS IN IMMUNOLOGY, 2017, 38 (07) :513-525

[8] LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration [J].

Deng, Mi ;

Gui, Xun ;

Kim, Jaehyup ;

Xie, Li ;

Chen, Weina ;

Li, Zunling ;

He, Licai ;

Chen, Yuanzhi ;

Chen, Heyu ;

Luo, Weiguang ;

Lu, Zhigang ;

Xie, Jingjing ;

Churchill, Hywyn ;

Xu, Yixiang ;

Zhou, Zhan ;

Wu, Guojin ;

Yu, Chenyi ;

John, Samuel ;

Hirayasu, Kouyuki ;

Nam Nguyen ;

Liu, Xiaoye ;

Huang, Fangfang ;

Li, Leike ;

Deng, Hui ;

Tang, Haidong ;

Sadek, Ali H. ;

Zhang, Lingbo ;

Huang, Tao ;

Zou, Yizhou ;

Chen, Benjamin ;

Zhu, Hong ;

Arase, Hisashi ;

Xia, Ningshao ;

Jiang, Youxing ;

Collins, Robert ;

You, M. James ;

Homsi, Jade ;

Unni, Nisha ;

Lewis, Cheryl ;

Chen, Guo-Qiang ;

Fu, Yang-Xin ;

Liao, X. Charlene ;

An, Zhiqiang ;

Zheng, Junke ;

Zhang, Ningyan ;

Zhang, Cheng Cheng .

NATURE, 2018, 562 (7728) :605-+

[9] A motif in LILRB2 critical for Angptl2 binding and activation [J].

Deng, Mi ;

Lu, Zhigang ;

Zheng, Junke ;

Wan, Xuan ;

Chen, Xiaoli ;

Hirayasu, Kouyuki ;

Sun, Hanzi ;

Lam, Yeeling ;

Chen, Liping ;

Wang, Qihui ;

Song, Chun ;

Huang, Niu ;

Gao, George F. ;

Jiang, Youxing ;

Arase, Hisashi ;

Zhang, Cheng Cheng .

BLOOD, 2014, 124 (06) :924-935

[10] Expression of immune inhibitory receptor ILT3 in acute myeloid leukemia with monocytic differentiation [J].

Dobrowolska, Hanna ;

Gill, Kamraan Z. ;

Serban, Geo ;

Ivan, Elena ;

Li, Qing ;

Qiao, Pengyuan ;

Suciu-Foca, Nicole ;

Savage, David ;

Alobeid, Bachir ;

Bhagat, Govind ;

Colovai, Adriana I. .

CYTOMETRY PART B-CLINICAL CYTOMETRY, 2013, 84B (01) :21-29

← 1 2 3 4 →