PO.ET02.02 · 实验与分子治疗
BCG042：一种具有ADCC增强的有前景的抗LILRB4抗体在单核细胞性AML临床前模型中展示出更优疗效
BCG042: A promising anti-LILRB4 antibody with ADCC enhancement demonstrates superior efficacy in preclinical models of monocytic AML
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
单核细胞性急性髓系白血病（AML；FAB M4/M5）是一种侵袭性疾病，其特征为对标准疗法（包括化疗以及去甲基化药物（HMA）联合维奈克拉）的应答有限。LILRB4是一种经验证的免疫抑制受体，在单核细胞性AML母细胞上高表达，通过与APOE结合和SHP-1/2信号传导驱动免疫逃逸和组织浸润。为克服当前疗法的局限性，我们改造了BCG042，一种全人源抗LILRB4 IgG1抗体，具有旨在增强效应功能和靶向清除AML细胞的Fc突变体。BCG042以纳摩尔亲和力与人LILRB4结合，对食蟹猴直系同源物具有交叉反应性，并在LILRB家族内表现出高度特异性。表位分箱分析证实BCG042与IO-202共享相同表位。BCG042对LILRB4阳性AML细胞系（THP-1、MV-4-11）表现出强结合，且关键的是，在体外1 μg/mL浓度下对APOE-LILRB4信号传导的抑制优于IO-202类似物。BCG042介导针对LILRB4+ AML细胞的强效抗体依赖性细胞毒性（ADCC），而无抗体依赖性细胞吞噬（ADCP）或补体依赖性细胞毒性（CDC）活性。这种细胞毒性在Fc增强的SI变体中进一步放大。该抗体表现出良好的生物物理特性和可开发性特征。在体内，BCG042在B-NDG小鼠的THP-1异种移植模型中诱导显著的剂量依赖性肿瘤消退（给药剂量为0.1、0.5和1 mg/kg，Q3D×2），明显优于IO-202类似物。这种强效抗肿瘤效应在良好的安全性特征下实现，表现为无体重减轻或全身毒性迹象。BCG042独特地将对LILRB4免疫抑制轴的靶向阻断与强效的Fc工程化ADCC效应相结合。这种双重作用机制转化为更优的抗肿瘤疗效和良好的治疗窗口。这些令人信服的数据为BCG042作为复发/难治性单核细胞性AML患者的新型疗法的临床开发提供了有力依据。
查看英文原文 English 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.
利益披露 Disclosure
J. Hsu, None..
P. Li, None..
Y. Guo, None.