Targeting the CXCR4 pathway using a novel anti-CXCR4 IgG1 antibody (PF-06747143) in chronic lymphocytic leukemia.
Targeting the CXCR4 pathway using a novel anti-CXCR4 IgG1 antibody (PF-06747143) in chronic lymphocytic leukemia.
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DOI：
10.1186/s13045-017-0435-x
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发表时间：
2017-05-19
影响因子：
28.5
通讯作者：
Castro JE
中科院分区：
文献类型：
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作者：
Kashyap MK;Amaya-Chanaga CI;Kumar D;Simmons B;Huser N;Gu Y;Hallin M;Lindquist K;Yafawi R;Choi MY;Amine AA;Rassenti LZ;Zhang C;Liu SH;Smeal T;Fantin VR;Kipps TJ;Pernasetti F;Castro JE
CXCR 4-CXCL 12轴在慢性淋巴细胞白血病（CLL）-微环境相互作用中起重要作用。CXCR 4的过表达已在包括CLL在内的不同血液恶性肿瘤中报道。促存活趋化因子CXCL 12与其同源受体CXCR 4的结合诱导细胞迁移。CXCL 12/CXCR 4信号轴促进细胞存活和增殖，并可能有助于白血病细胞向淋巴组织和骨髓的嗜性。因此，我们假设用IgG 1抗体PF-06747143靶向CXCR 4可能是CLL的有效治疗方法。在CLL微环境的体外模型中评估患者来源的原代CLL-B细胞的细胞毒性。分析PF-06747143的细胞死亡诱导及其干扰趋化因子CXCL 12诱导机制（包括迁移和F-肌动蛋白聚合）的潜力。在CLL小鼠异种移植肿瘤模型中测定PF-06747143的体内疗效。PF-06747143是一种新型人源化IgG 1 CXCR 4拮抗剂抗体，在存在或不存在基质细胞的情况下，均可诱导患者源性原代CLL-B细胞的细胞死亡。此外，抗体诱导的细胞死亡不依赖于CLL高风险预后标志物。细胞死亡机制依赖于CXCR 4表达，需要抗体二价，涉及活性氧产生，并且不需要半胱天冬酶激活，所有特征都使人联想到程序性细胞死亡（PCD）。PF-06747143还通过Fc驱动的抗体依赖性细胞介导的细胞毒性（ADCC）和补体依赖性细胞毒性活性（CDC）诱导强效B-CLL细胞毒性。PF-06747143与标准治疗（SOC）药物（包括利妥昔单抗、氟达拉滨（F-ara-A）、伊曲替尼和苯达莫司汀）在B-CLL治疗中具有显著的组合效应。在CLL异种移植模型中，PF-06747143单药治疗以及与苯达莫司汀联合治疗可降低肿瘤负荷并改善生存期。我们证明PF-06747143在CLL原代细胞中具有生物活性，支持评价PF-06747143治疗CLL患者的依据。本文的在线版本（doi：10.1186/s13045-017-0435-x）包含补充材料，可供授权用户使用。
The CXCR4-CXCL12 axis plays an important role in the chronic lymphocytic leukemia (CLL)-microenvironment interaction. Overexpression of CXCR4 has been reported in different hematological malignancies including CLL. Binding of the pro-survival chemokine CXCL12 with its cognate receptor CXCR4 induces cell migration. CXCL12/CXCR4 signaling axis promotes cell survival and proliferation and may contribute to the tropism of leukemia cells towards lymphoid tissues and bone marrow. Therefore, we hypothesized that targeting CXCR4 with an IgG1 antibody, PF-06747143, may constitute an effective therapeutic approach for CLL. Patient-derived primary CLL-B cells were assessed for cytotoxicity in an in vitro model of CLL microenvironment. PF-06747143 was analyzed for cell death induction and for its potential to interfere with the chemokine CXCL12-induced mechanisms, including migration and F-actin polymerization. PF-06747143 in vivo efficacy was determined in a CLL murine xenograft tumor model. PF-06747143, a novel-humanized IgG1 CXCR4 antagonist antibody, induced cell death of patient-derived primary CLL-B cells, in presence or absence of stromal cells. Moreover, cell death induction by the antibody was independent of CLL high-risk prognostic markers. The cell death mechanism was dependent on CXCR4 expression, required antibody bivalency, involved reactive oxygen species production, and did not require caspase activation, all characteristics reminiscent of programmed cell death (PCD). PF-06747143 also induced potent B-CLL cytotoxicity via Fc-driven antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity activity (CDC). PF-06747143 had significant combinatorial effect with standard of care (SOC) agents in B-CLL treatment, including rituximab, fludarabine (F-ara-A), ibrutinib, and bendamustine. In a CLL xenograft model, PF-06747143 decreased tumor burden and improved survival as a monotherapy, and in combination with bendamustine. We show evidence that PF-06747143 has biological activity in CLL primary cells, supporting a rationale for evaluation of PF-06747143 for the treatment of CLL patients. The online version of this article (doi:10.1186/s13045-017-0435-x) contains supplementary material, which is available to authorized users.