INSERM, UMR 1170, 114 rue Edouard Vaillant, 94805, Villejuif, France.
Université Paris-Saclay, Gustave Roussy, Villejuif, France.
Sci Rep. 2017 Aug 4;7(1):7305. doi: 10.1038/s41598-017-07848-8.
The chemokine receptor CXCR4 mediates cell anchorage in the bone marrow (BM) microenvironment and is overexpressed in 25-30% of patients with acute myeloid leukemia (AML). Here we have shown that a new CXCR4 receptor antagonist IgG1 antibody (PF-06747143) binds strongly to AML cell lines and to AML primary cells inhibiting their chemotaxis in response to CXCL12. PF-06747143 also induced cytotoxicity in AML cells via Fc-effector function. To characterize the effects of PF-06747143 on leukemia progression, we used two different patient-derived xenograft (PDX) models: Patient 17 and P15 models, characterized by relatively low and high CXCR4 expression, respectively. Weekly administration of PF-06747143 to leukemic mice significantly reduced leukemia development in both models. Secondary transplantation of BM cells from PF-06747143-treated or IgG1 control-treated animals showed that leukemic progenitors were also targeted by PF-06747143. Administration of a single dose of PF-06747143 to PDX models induced rapid malignant cell mobilization into the peripheral blood (PB). These findings support evaluation of this antibody in AML therapy, with particular appeal to patients resistant to chemotherapy and to unfit patients, unable to tolerate intensive chemotherapy.
趋化因子受体 CXCR4 介导细胞在骨髓（BM）微环境中的附着，并且在 25-30%的急性髓系白血病（AML）患者中过表达。在这里，我们已经表明，一种新型 CXCR4 受体拮抗剂 IgG1 抗体（PF-06747143）强烈结合 AML 细胞系和 AML 原代细胞，抑制它们对 CXCL12 的趋化反应。PF-06747143 还通过 Fc 效应功能诱导 AML 细胞的细胞毒性。为了表征 PF-06747143 对白血病进展的影响，我们使用了两种不同的患者来源的异种移植（PDX）模型：患者 17 模型和 P15 模型，分别具有相对较低和较高的 CXCR4 表达。每周向白血病小鼠给予 PF-06747143 可显著降低两种模型中的白血病发展。来自接受 PF-06747143 治疗或 IgG1 对照治疗的动物的 BM 细胞的二次移植表明，白血病祖细胞也被 PF-06747143 靶向。单次给予 PF-06747143 至 PDX 模型可诱导恶性细胞迅速动员到外周血（PB）中。这些发现支持在 AML 治疗中评估这种抗体，特别是对化疗耐药和不适合接受强化化疗的患者具有吸引力。
