Disrupting LILRB4/APOE Interaction by an Efficacious Humanized Antibody Reverses T-cell Suppression and Blocks AML Development.
(2019) Cancer Immunol Res 7: 1244-1257
Authors: 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., Liao, X.C., Xia, N., Gao, G.F., Zhang, N., Zhang, C.C., An, Z.
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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