A novel CXCR4 antagonist IgG1 antibody (PF-06747143) for the treatment of hematologic malignancies
العنوان: | A novel CXCR4 antagonist IgG1 antibody (PF-06747143) for the treatment of hematologic malignancies |
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المؤلفون: | Gretchen Jimenez, Rolla Yafawi, Shu-Hui Liu, David L. Shelton, Zhengming Yan, Wenlian Wang, Thomas-Toan Tran, Max Hallin, Tod Smeal, Sherman Michael Chin, Kevin Lindquist, Flavia Pernasetti, Mary E. Spilker, Justine L. Lam, Cathy Zhang, Nanni Huser, Eileen R. Blasi, Colleen Brown, Marco Costa, Brett H. Simmons, Bernadette Pascual, Yin Gu, Valeria Fantin, Jyothirmayee Kudaravalli, Wei-Hsien Ho, Conglin Fan, Ishita Barman, Jing-Tyan Ma |
المصدر: | Blood Advances. 1:1088-1100 |
بيانات النشر: | American Society of Hematology, 2017. |
سنة النشر: | 2017 |
مصطلحات موضوعية: | Lymphoid Neoplasia, CXCR4 antagonist, business.industry, Chronic lymphocytic leukemia, Myeloid leukemia, Hematology, Pharmacology, medicine.disease, CXCR4, Lymphoma, medicine.anatomical_structure, Cell killing, hemic and lymphatic diseases, Bone marrow neoplasm, medicine, Bone marrow, business |
الوصف: | 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). |
تدمد: | 2473-9537 2473-9529 |
URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4c77a0ec73307415cfe149a84856c66d https://doi.org/10.1182/bloodadvances.2016003921 |
حقوق: | OPEN |
رقم الأكسشن: | edsair.doi.dedup.....4c77a0ec73307415cfe149a84856c66d |
قاعدة البيانات: | OpenAIRE |
تدمد: | 24739537 24739529 |
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