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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-08-04

AUTHORS

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

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. More... »

PAGES

7305

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-017-07848-8

DOI

http://dx.doi.org/10.1038/s41598-017-07848-8

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1090990621

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28779088


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