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Cancer Immunol Res. 2019 Jun 18. doi: 10.1158/2326-6066.CIR-19-0036. [Epub ahead of print]

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

Gui X#1, Deng M#2, Song H3, Chen Y1,4, Xie J2,5, Li Z2,5, He L2,6, Huang F2,7, Xu Y1, Anami Y1, Yu H4, Yu C1,8, Li L1, Yuan Z1, Xu X9, Wang Q1,9, Chai Y9, Huang T10, Shi Y9, Tsuchikama K1, Liao XC10, Xia N4, Gao GF9,11, Zhang N12, Zhang CC13, An Z12.

Author information

1
Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas.
2
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas.
3
Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China.
4
School of Public Health, Xiamen University, Xiamen, Fujian, China.
5
Taishan Immunology Program, Basic Medicine School, Binzhou Medical University, Yantai, China.
6
Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medical and Life Science, Wenzhou Medical University, Wenzhou, China.
7
Department of Hematology, Zhongshan Hospital, Xiamen University, Xiamen, China.
8
School of Xiangya Medicine, Central South University, Changsha, Hunan, China.
9
CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
10
Immune-Onc Therapeutics, Inc., Palo Alto, California.
11
National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC), Beijing, China.
12
Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas. Zhiqiang.An@uth.tmc.edu Alec.Zhang@UTSouthwestern.edu Ningyan.Zhang@uth.tmc.edu.
13
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas. Zhiqiang.An@uth.tmc.edu Alec.Zhang@UTSouthwestern.edu Ningyan.Zhang@uth.tmc.edu.
#
Contributed equally

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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