Liu Shu-Hui, Gu Yin, Pascual Bernadette, Yan Zhengming, Hallin Max, Zhang Cathy, Fan Conglin, Wang Wenlian, Lam Justine, Spilker Mary E, Yafawi Rolla, Blasi Eileen, Simmons Brett, Huser Nanni, Ho Wei-Hsien, Lindquist Kevin, Tran Thomas-Toan, Kudaravalli Jyothirmayee, Ma Jing-Tyan, Jimenez Gretchen, Barman Ishita, Brown Colleen, Chin Sherman Michael, Costa Maria J, Shelton David, Smeal Tod, Fantin Valeria R, Pernasetti Flavia
Oncology Research & Development, Pfizer Worldwide Research & Development, South San Francisco, CA; and.
Oncology Research & Development.
Blood Adv. 2017 Jun 21;1(15):1088-1100. doi: 10.1182/bloodadvances.2016003921. eCollection 2017 Jun 27.
The chemokine receptor CXCR4 is highly expressed and associated with poor prognosis in multiple malignancies. Upon engagement by its ligand, CXCL12, CXCR4 triggers intracellular signaling pathways that control trafficking of cells to tissues where the ligand is expressed, such as the bone marrow (BM). In hematologic cancers, CXCR4-driven homing of malignant cells to the BM protective niche is a key mechanism driving disease and therapy resistance. We developed a humanized CXCR4 immunoglobulin G1 (IgG1) antibody (Ab), PF-06747143, which binds to CXCR4 and inhibits CXCL12-mediated signaling pathways, as well as cell migration. In in vivo preclinical studies, PF-06747143 monotherapy rapidly and transiently mobilized cells from the BM into the peripheral blood. In addition, PF-06747143 effectively induced tumor cell death via its Fc constant region-mediated effector function. This Fc-mediated cell killing mechanism not only enhanced antitumor efficacy, but also played a role in reducing the duration of cell mobilization, when compared with an IgG4 version of the Ab, which does not have Fc-effector function. PF-06747143 treatment showed strong antitumor effect in multiple hematologic tumor models including non-Hodgkin lymphoma (NHL), acute myeloid leukemia (AML), and multiple myeloma (MM). Importantly, PF-06747143 synergized with standard-of-care agents in a chemoresistant AML patient-derived xenograft model and in an MM model. These findings suggest that PF-06747143 is a potential best-in-class anti-CXCR4 antagonist for the treatment of hematologic malignancies, including in the resistant setting. PF-06747143 is currently in phase 1 clinical trial evaluation (registered at www.clinicaltrials.gov as #NCT02954653).
趋化因子受体CXCR4在多种恶性肿瘤中高表达且与预后不良相关。在与配体CXCL12结合后，CXCR4触发细胞内信号通路，该通路控制细胞向配体表达组织（如骨髓）的迁移。在血液系统癌症中，CXCR4驱动恶性细胞归巢至骨髓保护性微环境是导致疾病和治疗耐药的关键机制。我们研发了一种人源化CXCR4免疫球蛋白G1（IgG1）抗体（Ab）PF-06747143，它能与CXCR4结合并抑制CXCL12介导的信号通路以及细胞迁移。在体内临床前研究中，PF-06747143单药治疗迅速且短暂地将骨髓中的细胞动员至外周血。此外，PF-06747143通过其Fc恒定区介导的效应功能有效诱导肿瘤细胞死亡。与不具有Fc效应功能的IgG4型抗体相比，这种Fc介导的细胞杀伤机制不仅增强了抗肿瘤疗效，还在缩短细胞动员持续时间方面发挥了作用。PF-06747143治疗在包括非霍奇金淋巴瘤（NHL）、急性髓系白血病（AML）和多发性骨髓瘤（MM）在内的多种血液系统肿瘤模型中显示出强大的抗肿瘤作用。重要的是，在化疗耐药的AML患者来源异种移植模型和MM模型中，PF-06747143与标准治疗药物具有协同作用。这些发现表明，PF-06747143是一种潜在的同类最佳抗CXCR4拮抗剂，用于治疗血液系统恶性肿瘤，包括耐药情况。PF-06747143目前正在进行1期临床试验评估（在www.clinicaltrials.gov上注册为#NCT02954653）。
