A New Anti-CXCR4 Antibody That Blocks the CXCR4/SDF-1 Axis and Mobilizes Effector Cells.
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.
Department of Experimental Oncology, Centre d'Immunologie Pierre Fabre (CIPF), Saint-Julien-en-Genevois, France.
Matthieu
M
Broussas
Unit of Molecular and Cellular Biology, CIPF, Saint-Julien-en-Genevois, France.
Nicolas
N
Boute
Department of Experimental Oncology, Centre d'Immunologie Pierre Fabre (CIPF), Saint-Julien-en-Genevois, France.
Barbara
B
Akla
Unit of Molecular and Cellular Biology, CIPF, Saint-Julien-en-Genevois, France.
Sven
S
Berger
Department of Experimental Oncology, Centre d'Immunologie Pierre Fabre (CIPF), Saint-Julien-en-Genevois, France.
Charlotte
C
Beau-Larvor
Department of Physico-chemistry, CIPF, Saint-Julien-en-Genevois, France.
Thierry
T
Champion
Unit of Molecular and Cellular Biology, CIPF, Saint-Julien-en-Genevois, France.
Alain
A
Robert
Department of Physico-chemistry, CIPF, Saint-Julien-en-Genevois, France.
Alain
A
Beck
Department of Biochemistry, CIPF, Saint-Julien-en-Genevois, France.
Jean-François
JF
Haeuw
Department of Experimental Oncology, Centre d'Immunologie Pierre Fabre (CIPF), Saint-Julien-en-Genevois, France.
Liliane
L
Goetsch
Contract Development and Manufacturing Organization, Toulouse, France.
Christian
C
Bailly
INSERM 1052/CNRS 5286/University of Lyon, Lyon, France.
Charles
C
Dumontet
Hematology Service and Service of Clinical Pathology, University Hospital Geneva, Geneva, Switzerland.
Thomas
T
Matthes
CIPF Director, Saint-Julien-en-Genevois, France.
Nathalie
N
Corvaia
Department of Physico-chemistry, CIPF, Saint-Julien-en-Genevois, France. christine.klinguer.hamour@pierre-fabre.com.
Christine
C
Klinguer-Hamour
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism*; D003165:Complement System Proteins / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D055503:Protein Multimerization; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000071560:beta-Arrestin 2 / Q000378:metabolism
D000911:Antibodies, Monoclonal; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D000071560:beta-Arrestin 2; D003165:Complement System Proteins