Abstract Monocytic acute myeloid leukemia (AML; FAB M4/M5) is an aggressive disease characterized by limited response to standard therapies, including chemotherapy and hypomethylating agent (HMA) plus venetoclax combinations. LILRB4, a validated immunosuppressive receptor highly expressed on monocytic AML blasts, drives immune evasion and tissue infiltration via APOE engagement and SHP-1/2 signaling. To overcome the limitations of current therapy, we engineered BCG042, a fully human anti-LILRB4 IgG1 antibody with an Fc mutant designed to enhance effector function and targeted clearance of AML cells. BCG042 binds to human LILRB4 with nanomolar affinity, demonstrates cross-reactivity to the cynomolgus ortholog, and exhibits high specificity within the LILRB family. Epitope binning analysis confirmed that BCG042 shares the same epitope as IO-202. BCG042 demonstrated strong binding to LILRB4-positive AML cell lines (THP-1, MV-4-11), and critically, exhibited superior inhibition of APOE-LILRB4 signaling compared to an IO-202 analog at 1 µg/mL in vitro. BCG042 mediated robust antibody-dependent cellular cytotoxicity (ADCC) against LILRB4+ AML cells, without antibody-dependent cellular phagocytosis (ADCP) or complement-dependent cytotoxicity (CDC) activity. This cytotoxicity was further amplified in an Fc-enhanced SI variant. This antibody exhibits favorable biophysical properties and developability profiles. In vivo, BCG042 induced significant dose-dependent tumor regression in a THP-1 xenograft model in B-NDG mice (dosed at 0.1, 0.5, and 1 mg/kg, Q3D×2), markedly outperforming an IO-202 analog. This potent antitumor effect was achieved with a favorable safety profile, evidenced by no body weight loss or signs of systemic toxicity. BCG042 uniquely combines targeted blockade of the LILRB4 immunosuppressive axis with potent Fc-engineered ADCC effect. This dual mechanism of action translates into superior antitumor efficacy and a favorable therapeutic window in preclinical models. These compelling data provide a strong rationale for the clinical development of BCG042 as a novel therapeutic for patients with relapsed/refractory monocytic AML. Citation Format: Jade Hsu, Peiran Li, Yanan Guo. BCG042: A promising anti-LILRB4 antibody with ADCC enhancement demonstrates superior efficacy in preclinical models of monocytic AML abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1709.
Hsu et al. (Fri,) studied this question.