Targeting primary acute myeloid leukemia with a new CXCR4 antagonist IgG1 antibody (PF-06747143)

Targeting primary acute myeloid leukemia with a new CXCR4 antagonist IgG1 antibody (PF-06747143)

Abstract 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 an...

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Autores principales: Yanyan Zhang, Erika Saavedra, Ruoping Tang, Yin Gu, Patrick Lappin, Dusko Trajkovic, Shu-Hui Liu, Tod Smeal, Valeria Fantin, Stephane De Botton, Ollivier Legrand, Francois Delhommeau, Flavia Pernasetti, Fawzia Louache
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Publicado: Nature Portfolio 2017
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Acceso en línea:https://doaj.org/article/49dab6606e4e44f2902c2a6f96a70cff
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spelling oai:doaj.org-article:49dab6606e4e44f2902c2a6f96a70cff2021-12-02T15:05:57ZTargeting primary acute myeloid leukemia with a new CXCR4 antagonist IgG1 antibody (PF-06747143)10.1038/s41598-017-07848-82045-2322https://doaj.org/article/49dab6606e4e44f2902c2a6f96a70cff2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07848-8https://doaj.org/toc/2045-2322Abstract 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 17CXCR4-low and P15CXCR4-high 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.Yanyan ZhangErika SaavedraRuoping TangYin GuPatrick LappinDusko TrajkovicShu-Hui LiuTod SmealValeria FantinStephane De BottonOllivier LegrandFrancois DelhommeauFlavia PernasettiFawzia LouacheNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Yanyan Zhang
Erika Saavedra
Ruoping Tang
Yin Gu
Patrick Lappin
Dusko Trajkovic
Shu-Hui Liu
Tod Smeal
Valeria Fantin
Stephane De Botton
Ollivier Legrand
Francois Delhommeau
Flavia Pernasetti
Fawzia Louache
Targeting primary acute myeloid leukemia with a new CXCR4 antagonist IgG1 antibody (PF-06747143)
description Abstract 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 17CXCR4-low and P15CXCR4-high 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.
format article
author Yanyan Zhang
Erika Saavedra
Ruoping Tang
Yin Gu
Patrick Lappin
Dusko Trajkovic
Shu-Hui Liu
Tod Smeal
Valeria Fantin
Stephane De Botton
Ollivier Legrand
Francois Delhommeau
Flavia Pernasetti
Fawzia Louache
author_facet Yanyan Zhang
Erika Saavedra
Ruoping Tang
Yin Gu
Patrick Lappin
Dusko Trajkovic
Shu-Hui Liu
Tod Smeal
Valeria Fantin
Stephane De Botton
Ollivier Legrand
Francois Delhommeau
Flavia Pernasetti
Fawzia Louache
author_sort Yanyan Zhang
title Targeting primary acute myeloid leukemia with a new CXCR4 antagonist IgG1 antibody (PF-06747143)
title_short Targeting primary acute myeloid leukemia with a new CXCR4 antagonist IgG1 antibody (PF-06747143)
title_full Targeting primary acute myeloid leukemia with a new CXCR4 antagonist IgG1 antibody (PF-06747143)
title_fullStr Targeting primary acute myeloid leukemia with a new CXCR4 antagonist IgG1 antibody (PF-06747143)
title_full_unstemmed Targeting primary acute myeloid leukemia with a new CXCR4 antagonist IgG1 antibody (PF-06747143)
title_sort targeting primary acute myeloid leukemia with a new cxcr4 antagonist igg1 antibody (pf-06747143)
publisher Nature Portfolio
publishDate 2017
url https://doaj.org/article/49dab6606e4e44f2902c2a6f96a70cff
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