Targeting the CXCR4 pathway using a novel anti-CXCR4 IgG1 antibody (PF-06747143) in chronic lymphocytic leukemia

Journal of Hematology & Oncology
Manoj K KashyapJanuario E Castro

Abstract

The CXCR4-CXCL12 axis plays an important role in the chronic lymphocytic leukemia (CLL)-microenvironment interaction. Overexpression of CXCR4 has been reported in different hematological malignancies including CLL. Binding of the pro-survival chemokine CXCL12 with its cognate receptor CXCR4 induces cell migration. CXCL12/CXCR4 signaling axis promotes cell survival and proliferation and may contribute to the tropism of leukemia cells towards lymphoid tissues and bone marrow. Therefore, we hypothesized that targeting CXCR4 with an IgG1 antibody, PF-06747143, may constitute an effective therapeutic approach for CLL. Patient-derived primary CLL-B cells were assessed for cytotoxicity in an in vitro model of CLL microenvironment. PF-06747143 was analyzed for cell death induction and for its potential to interfere with the chemokine CXCL12-induced mechanisms, including migration and F-actin polymerization. PF-06747143 in vivo efficacy was determined in a CLL murine xenograft tumor model. PF-06747143, a novel-humanized IgG1 CXCR4 antagonist antibody, induced cell death of patient-derived primary CLL-B cells, in presence or absence of stromal cells. Moreover, cell death induction by the antibody was independent of CLL high-risk prognost...Continue Reading

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Citations

Feb 2, 2018·Frontiers in Immunology·Carlos Cuesta-MateosCecilia Muñoz-Calleja
May 31, 2019·Clinical Reviews in Allergy & Immunology·Anne BordronYves Renaudineau
Mar 9, 2018·Oncotarget·Maria BreunCarsten Hagemann
Sep 5, 2019·Molecular Pharmacology·Vladimir BobkovMartine J Smit
Oct 22, 2020·International Journal of Molecular Sciences·Fátima Bayón-CalderónSara González-García
Oct 27, 2020·Journal of Leukocyte Biology·Gary D LukerJohann Zimmermann
Apr 23, 2021·Haematologica·Rebecka SvanbergCarsten U Niemann

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Methods Mentioned

BETA
xenograft
flow cytometry
surface
biosensor
FACS
Assay
bioluminescence imaging
surface plasmon resonance

Clinical Trials Mentioned

NCT02954653

Software Mentioned

FlowJo
GraphPad Prism
Biacore T200 Evaluation
CompuSyn

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