Department of Chemistry and Applied Biosciences, ETH Zürich, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, Switzerland.
Sci Transl Med. 2013 Sep 4;5(201):201ra118. doi: 10.1126/scitranslmed.3006221.
Acute myeloid leukemia (AML) is a rapidly progressing disease that is accompanied by a strong increase in microvessel density in the bone marrow. This observation prompted us to stain biopsies of AML and acute lymphoid leukemia (ALL) patients with the clinical-stage human monoclonal antibodies F8, L19, and F16 directed against markers of tumor angiogenesis. The analysis revealed that the F8 and F16 antibodies strongly stained 70% of AML and 75% of ALL bone marrow specimens, whereas chloroma biopsies were stained with all three antibodies. Therapy experiments performed in immunocompromised mice bearing human NB4 leukemia with the immunocytokine F8-IL2 [consisting of the F8 antibody fused to human interleukin-2 (IL-2)] mediated a strong inhibition of AML progression. This effect was potentiated by the addition of cytarabine, promoting complete responses in 40% of treated animals. Experiments performed in immunocompetent mice bearing C1498 murine leukemia revealed long-lasting complete tumor eradication in all treated mice. The therapeutic effect of F8-IL2 was mediated by both natural killer cells and CD8(+) T cells, whereas CD4(+) T cells appeared to be dispensable, as determined in immunodepletion experiments. The treatment of an AML patient with disseminated extramedullary AML manifestations with F16-IL2 (consisting of the F16 antibody fused to human IL-2, currently being tested in phase 2 clinical trials in patients with solid tumors) and low-dose cytarabine showed significant reduction of AML lesions and underlines the translational potential of vascular tumor-targeting antibody-cytokine fusions for the treatment of patients with leukemia.
急性髓细胞白血病（AML）是一种快速进展的疾病，其骨髓中微血管密度会强烈增加。这一观察结果促使我们用针对肿瘤血管生成标志物的临床阶段人源单克隆抗体 F8、L19 和 F16 对 AML 和急性淋巴细胞白血病（ALL）患者的活检进行染色。分析表明，F8 和 F16 抗体强烈染色了 70%的 AML 和 75%的 ALL 骨髓标本，而绿色瘤活检则用这三种抗体染色。用免疫细胞因子 F8-IL2（由与人类白细胞介素-2（IL-2）融合的 F8 抗体组成）对携带人 NB4 白血病的免疫功能低下小鼠进行的治疗实验强烈抑制了 AML 的进展。添加阿糖胞苷可增强这种作用，促进 40%接受治疗的动物产生完全反应。在携带 C1498 鼠白血病的免疫功能正常的小鼠中进行的实验显示，所有接受治疗的小鼠均能持久完全消除肿瘤。F8-IL2 的治疗效果是通过自然杀伤细胞和 CD8(+)T 细胞介导的，而 CD4(+)T 细胞似乎是可有可无的，这在免疫耗竭实验中得到了证实。用 F16-IL2（由与人类白细胞介素-2 融合的 F16 抗体组成，目前正在实体瘤患者的 2 期临床试验中进行测试）和低剂量阿糖胞苷治疗患有播散性骨髓外 AML 表现的 AML 患者，显示 AML 病变明显减少，强调了血管肿瘤靶向抗体-细胞因子融合物用于治疗白血病患者的转化潜力。
