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 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.
Type de document :
Article dans une revue
Scientific Reports, Nature Publishing Group, 2017, 7, pp.7305. 〈10.1038/s41598-017-07848-8〉
Liste complète des métadonnées

Littérature citée [36 références]  Voir  Masquer  Télécharger

http://hal.upmc.fr/hal-01580202
Contributeur : Gestionnaire Hal-Upmc <>
Soumis le : vendredi 1 septembre 2017 - 10:57:17
Dernière modification le : jeudi 11 janvier 2018 - 06:28:13

Fichier

s41598-017-07848-8.pdf
Publication financée par une institution

Licence


Distributed under a Creative Commons Paternité 4.0 International License

Identifiants

Collections

Citation

Yanyan Zhang, Erika Saavedra, Ruoping Tang, Yin Gu, Patrick Lappin, et al.. Targeting primary acute myeloid leukemia with a new CXCR4 antagonist IgG1 antibody (PF-06747143). Scientific Reports, Nature Publishing Group, 2017, 7, pp.7305. 〈10.1038/s41598-017-07848-8〉. 〈hal-01580202〉

Partager

Métriques

Consultations de la notice

163

Téléchargements de fichiers

34