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 development of monocytic AML in various models including patient-derived xenograft (PDX) 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: 1) reversal of T cell suppression; 2) inhibition of monocytic AML cell tissue infiltration; 3) antibody-dependent cellular cytotoxicity (ADCC); and 4) antibody dependent cellular phagocytosis (ADCP). Therefore, targeting LILRB4 with antibody represents an effective therapeutic strategy for treating monocytic AML.