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

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