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Title

A New Anti-CXCR4 Antibody That Blocks the CXCR4/SDF-1 Axis and Mobilizes Effector Cells

Authors
Broussas, Matthieu
Boute, Nicolas
Akla, Barbara
Berger, Sven
Beau-Larvor, Charlotte
Champion, Thierry
Robert, Alain
Beck, Alain
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Published in Molecular Cancer Therapeutics. 2016, vol. 15, no. 8, p. 1890-1899
Abstract The type IV C-X-C-motif chemokine receptor (CXCR4) is expressed in a large variety of human cancers, including hematologic malignancies, and this receptor and its ligand, stromal cell-derived factor-1 (SDF-1), play a crucial role in cancer progression. We generated a humanized immunoglobulin G1 mAb, hz515H7, which binds human CXCR4, efficiently competes for SDF-1 binding, and induces a conformational change in CXCR4 homodimers. Furthermore, it inhibits both CXCR4 receptor-mediated G-protein activation and β-arrestin-2 recruitment following CXCR4 activation. The binding of the hz515H7 antibody to CXCR4 inhibits the SDF-1-induced signaling pathway, resulting in reduced phosphorylation of downstream effectors, such as Akt, Erk1/2, p38, and GSK3β. Hz515H7 also strongly inhibits cell migration and proliferation and, while preserving normal blood cells, induces both antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against neoplastic cells. In mouse xenograft models, hz515H7 displays antitumor activities with multiple hematologic tumor cell lines, with its Fc-mediated effector functions proving essential in this context. Furthermore, hz515H7 binds to primary tumor cells from acute myeloid leukemia and multiple myeloma patients. Collectively, our results demonstrate two major mechanisms of action, making hz515H7 unique in this regard. Its potential as a best-in-class molecule is currently under investigation in a phase I clinical trial. Mol Cancer Ther; 15(8); 1890-9. ©2016 AACR.
Identifiers
PMID: 27297868
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Article (Published version) (1.2 MB) - public document Free access
Structures
Research group Analyses cellulaires et moléculaires des hémopathies malignes (929)
Project Bourse du Centre d'Immunologie Pierre Fabre
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BROUSSAS, Matthieu et al. A New Anti-CXCR4 Antibody That Blocks the CXCR4/SDF-1 Axis and Mobilizes Effector Cells. In: Molecular Cancer Therapeutics, 2016, vol. 15, n° 8, p. 1890-1899. https://archive-ouverte.unige.ch/unige:88986

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Deposited on : 2016-11-16

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