Acute lymphoblastic leukemia (ALL) arises from the uncontrolled proliferation of B-cell precursors (BCP-ALL) or T cells (T-ALL). Current treatment protocols obtain high cure rates in children but are based on toxic polychemotherapy. Novel therapies are urgently needed, especially in relapsed/refractory (R/R) disease, high-risk (HR) leukemias and T-ALL, in which immunotherapy approaches remain scarce. Although the interleukin-7 receptor (IL-7R) plays a pivotal role in ALL development, no IL-7R–targeting immunotherapy has yet reached clinical application in ALL. The IL-7Rα chain (CD127)–targeting IgG4 antibody lusvertikimab (LUSV; formerly OSE-127) is a full antagonist of the IL-7R pathway, showing a good safety profile in healthy volunteers. Here, we show that ∼85% of ALL cases express surface CD127. We demonstrate significant in vivo efficacy of LUSV immunotherapy in a heterogeneous cohort of xenograft derived from patients (PDX) with BCP- and T-ALL in minimal residual disease (MRD) and overt leukemia models, including R/R and HR leukemias. Importantly, LUSV was particularly effective when combined with polychemotherapy in a phase 2-like PDX study with CD127 samples leading to MRD-negativity in >50% of mice treated with combination therapy. Mechanistically, LUSV targeted ALL cells via a dual mode of action comprising direct IL-7R antagonistic activity and induction of macrophage-mediated antibody-dependent cellular phagocytosis (ADCP). LUSV–mediated in vitro ADCP levels significantly correlated with CD127 expression levels and the reduction of leukemia burden upon treatment of PDX animals in vivo. Altogether, through its dual mode of action and good safety profile, LUSV may represent a novel immunotherapy option for any CD127 ALL, particularly in combination with standard-of-care polychemotherapy.

中文翻译：

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IL-7R 拮抗剂 lusvertikimab 通过抗体依赖性细胞吞噬作用降低异种移植 ALL 的白血病负担

急性淋巴细胞白血病 (ALL) 是由 B 细胞前体 (BCP-ALL) 或 T 细胞 (T-ALL) 不受控制的增殖引起的。目前的治疗方案在儿童中获得了很高的治愈率，但基于毒性多化疗。迫切需要新的治疗方法，特别是在复发/难治性 (R/R) 疾病、高危 (HR) 白血病和 T-ALL 方面，免疫治疗方法仍然稀缺。尽管白细胞介素7受体（IL-7R）在ALL发展中发挥着关键作用，但目前还没有针对IL-7R的免疫疗法在ALL中达到临床应用。 IL-7Rα 链 (CD127) 靶向 IgG4 抗体 lusvertikimab（LUSV；以前称为 OSE-127）是 IL-7R 通路的完全拮抗剂，在健康志愿者中显示出良好的安全性。在这里，我们发现约 85% 的 ALL 病例表达表面 CD127。我们在微小残留病 (MRD) 和显性白血病模型（包括 R/R 和 HR 白血病）中的 BCP 和 T-ALL 患者 (PDX) 异种移植物中证明了 LUSV 免疫疗法的显着体内疗效。重要的是，在一项类似 2 期 PDX 研究中，使用 CD127 样本与联合化疗联合使用 LUSV 时特别有效，导致超过 50% 接受联合治疗的小鼠出现 MRD 阴性。从机制上讲，LUSV 通过双重作用模式靶向 ALL 细胞，包括直接 IL-7R 拮抗活性和诱导巨噬细胞介导的抗体依赖性细胞吞噬作用 (ADCP)。 LUSV 介导的体外 ADCP 水平与 CD127 表达水平以及 PDX 动物体内治疗后白血病负担的减少显着相关。总而言之，通过其双重作用模式和良好的安全性，LUSV 可能代表任何 CD127 ALL 的新型免疫治疗选择，特别是与标准化疗联合治疗。