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

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.