title: Enhancement of the anti-tumor activity of therapeutic monoclonal antibodies by CXCR4 antagonists.
abstract: The interaction between CXCR4 on the surface of tumor cells and CXCL12 in the stroma is believed to contribute to tumor cell survival and protection against drug treatment. Inhibition of stromal survival signals by CXCR4 antagonists has been reported to render tumor cells more sensitive to chemotherapy, but little is known about potential synergy with monoclonal antibodies. In this study, administration of the small molecule CXCR4 antagonists plerixafor and GENZ-644494 was found to enhance the anti-tumor activity of the monoclonal antibodies alemtuzumab and rituximab in disseminated lymphoma models. The observed enhancement in therapeutic efficacy by CXCR4 antagonists appeared to involve several factors, including interference with the tumor-promoting signals delivered by CXCL12, disruption of the tumor/stroma interaction and mobilization of effector neutrophils capable of mediating antibody-dependent cell-mediated cytotoxicity. The involvement of neutrophils was further supported by the observed reversal in therapeutic benefit upon neutrophil depletion.
authors: Genzyme Corporation, Framingham, MA 01701, USA.
authors: Yanping
authors: Y
authors: Hu
authors: Matthew
authors: M
authors: Gale
authors: Jacqueline
authors: J
authors: Shields
authors: Carrie
authors: C
authors: Garron
authors: Mark
authors: M
authors: Swistak
authors: Tri-Hung
authors: TH
authors: Nguyen
authors: Gary
authors: G
authors: Jacques
authors: Robert
authors: R
authors: Fogle
authors: William
authors: W
authors: Siders
authors: Johanne
authors: J
authors: Kaplan
mesh_terms: D000074323:Alemtuzumab; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001596:Benzylamines; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D000080027:Cyclams; D004357:Drug Synergism; D005434:Flow Cytometry; D006571:Heterocyclic Compounds / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069283:Rituximab; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; C503590:N-(1,4,8,11- tetraazacyclotetradecanyl-1,4-phenylenebis(methylene))-2-(aminomethyl)- pyridine; D011725:Pyridines; D019718:Receptors, CXCR4; D000074323:Alemtuzumab; D000069283:Rituximab; C088327:plerixafor