Acute myeloid leukemia (AML) is the most common and aggressive blood cancer in adults. In particular, significant unmet medical needs exist for effective treatment strategies for acute myelomonocytic leukemia (M4) and acute monocytic leukemia (M5) AML subtypes. Antibody–drug conjugates (ADC) are a promising drug class for AML therapy, as demonstrated by the FDA-approved anti-CD33 ADC, gemtuzumab ozogamicin (Mylotarg). However, CD33 is expressed in normal hematopoietic stem cells, highlighting the critical need to identify AML-specific targets to minimize the risk of potential adverse effects. We have demonstrated that the leukocyte immunoglobulin-like receptor subfamily B4 (LILRB4) is expressed at significantly higher levels on monocytic M4 and M5 AML cells than on normal counterparts. Here, we test whether LILRB4 is a promising ADC target to kill monocytic AML cells while sparing healthy counterparts. To this end, we generated ADCs from a humanized anti-LILRB4 mAb and the antimitotic payload, monomethyl auristatin F. The conjugates constructed were characterized and evaluated for LILRB4-specific cell killing potency, toxicity to progenitor cells, pharmacokinetics, and therapeutic efficacy. Our ADC linker technology platform efficiently generated homogeneous anti-LILRB4 ADCs with defined drug-to-antibody ratios. The homogeneous anti-LILRB4 ADCs demonstrated the capacity for LILRB4-mediated internalization, suitable physicochemical properties, and high cell killing potency against LILRB4-positive AML cells. Importantly, our data indicate that these ADCs spare normal progenitor cells. One of our homogeneous conjugates exerted a remarkable therapeutic effect and no significant toxicity in a xenograft mouse model of disseminated human AML. Our findings highlight the clinical potential of anti-LILRB4 ADCs in monocytic AML therapy.

中文翻译：

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LILRB4-靶向抗体-药物偶联物用于治疗急性髓系白血病

急性髓性白血病 (AML) 是成人中最常见和最具侵袭性的血癌。特别是，对于急性髓单核细胞白血病 (M4) 和急性单核细胞白血病 (M5) AML 亚型的有效治疗策略，存在显着未满足的医疗需求。正如 FDA 批准的抗 CD33 ADC gemtuzumab ozogamicin (Mylotarg) 所证明的，抗体-药物偶联物 (ADC) 是一种有前途的 AML 治疗药物。然而，CD33 在正常造血干细胞中表达，突出了识别 AML 特异性靶标以最大程度降低潜在不良反应风险的迫切需要。我们已经证明，白细胞免疫球蛋白样受体亚家族 B4 (LILRB4) 在单核细胞 M4 和 M5 AML 细胞上的表达水平明显高于正常对应物。这里，我们测试 LILRB4 是否是一个有前途的 ADC 靶标，可以杀死单核细胞 AML 细胞，同时保留健康的对应物。为此，我们从人源化抗 LILRB4 mAb 和抗有丝分裂有效负载单甲基 auristatin F 生成 ADC。对构建的偶联物进行了表征和评估 LILRB4 特异性细胞杀伤效力、对祖细胞的毒性、药代动力学和治疗功效。我们的 ADC 连接器技术平台有效地生成具有确定的药物与抗体比率的均质抗 LILRB4 ADC。均质抗 LILRB4 ADC 证明了 LILRB4 介导的内化能力、合适的物理化学特性以及对 LILRB4 阳性 AML 细胞的高细胞杀伤效力。重要的是，我们的数据表明这些 ADC 可以保护正常祖细胞。我们的一种均质缀合物在播散性人类 AML 的异种移植小鼠模型中发挥了显着的治疗效果并且没有显着的毒性。我们的研究结果突出了抗 LILRB4 ADC 在单核细胞 AML 治疗中的临床潜力。