title: Antitumor effects of a monoclonal antibody to human CCR9 in leukemia cell xenografts.
abstract: Tumor expression of certain chemokine receptors is associated with resistance to apoptosis, migration, invasiveness and metastasis. Because CCR9 chemokine receptor expression is very restricted in healthy tissue, whereas it is present in tumors of distinct origins including leukemias, melanomas, prostate and ovary carcinomas, it can be considered a suitable candidate for target-directed therapy. Here, we report the generation and characterization of 91R, a mouse anti-human CCR9 IgG2b monoclonal antibody that recognizes an epitope within the CCR9 N-terminal domain. This antibody inhibits the growth of subcutaneous xenografts from human acute T lymphoblastic leukemia MOLT-4 cells in immunodeficient Rag2(-/-) mice. Tumor size in 91R-treated mice was reduced by 85% compared with isotype-matched antibody-treated controls. Tumor reduction in 91R-treated mice was concomitant with an increase in the apoptotic cell fraction and tumor necrotic areas, as well as a decrease in the fraction of proliferating cells and in tumor vascularization. In the presence of complement or murine natural killer cells, 91R promoted in vitro lysis of MOLT-4 leukemia cells, indicating that this antibody might eliminate tumor cells via complement- and cell-dependent cytotoxicity. The results show the potential of the 91R monoclonal antibody as a therapeutic agent for treatment of CCR9-expressing tumors.
authors.affiliation: Department of Immunology and Oncology; Centro Nacional de Biotecnología; Consejo Superior de Investigaciones Científicas (CNB/CSIC); Madrid, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Chamorro
authors.affiliation: Department of Immunology and Oncology; Centro Nacional de Biotecnología; Consejo Superior de Investigaciones Científicas (CNB/CSIC); Madrid, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Vela
authors.affiliation: Department of Immunology and Oncology; Centro Nacional de Biotecnología; Consejo Superior de Investigaciones Científicas (CNB/CSIC); Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Franco-Villanueva
authors.affiliation: Department of Immunology and Oncology; Centro Nacional de Biotecnología; Consejo Superior de Investigaciones Científicas (CNB/CSIC); Madrid, Spain; Current Affiliation: Centro Nacional de Investigaciones Cardiovasculares; Instituto de Salud Carlos III (CNIC/ISCIII); Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Carramolino
authors.affiliation: Department of Immunology and Oncology; Centro Nacional de Biotecnología; Consejo Superior de Investigaciones Científicas (CNB/CSIC); Madrid, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Gutiérrez
authors.affiliation: Department of Immunology and Oncology; Centro Nacional de Biotecnología; Consejo Superior de Investigaciones Científicas (CNB/CSIC); Madrid, Spain; Protein Tools Unit; Centro Nacional de Biotecnología; Consejo Superior de Investigaciones Científicas (CNB/CSIC); Madrid, Spain.
authors.forename: Lucio
authors.initials: L
authors.lastname: Gómez
authors.affiliation: Department of Immunology and Oncology; Centro Nacional de Biotecnología; Consejo Superior de Investigaciones Científicas (CNB/CSIC); Madrid, Spain; Protein Tools Unit; Centro Nacional de Biotecnología; Consejo Superior de Investigaciones Científicas (CNB/CSIC); Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Lozano
authors.affiliation: Department of Plant Molecular Genetics; Centro Nacional de Biotecnología; Consejo Superior de Investigaciones Científicas (CNB/CSIC); Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Salvador
authors.affiliation: Protein Tools Unit; Centro Nacional de Biotecnología; Consejo Superior de Investigaciones Científicas (CNB/CSIC); Madrid, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: García-Gallo
authors.affiliation: Department of Immunology and Oncology; Centro Nacional de Biotecnología; Consejo Superior de Investigaciones Científicas (CNB/CSIC); Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Martínez-A
authors.affiliation: Department of Immunology and Oncology; Centro Nacional de Biotecnología; Consejo Superior de Investigaciones Científicas (CNB/CSIC); Madrid, Spain; Protein Tools Unit; Centro Nacional de Biotecnología; Consejo Superior de Investigaciones Científicas (CNB/CSIC); Madrid, Spain.
authors.forename: Leonor
authors.initials: L
authors.lastname: Kremer
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000276:immunology / Q000494:pharmacology*; D000912:Antibodies, Neoplasm / Q000276:immunology / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology*; D019169:Jurkat Cells; D007938:Leukemia / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D017434:Protein Structure, Tertiary; D054388:Receptors, CCR / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; C119309:CC chemokine receptor 9; D007074:Immunoglobulin G; D054388:Receptors, CCR
keywords: cell-mediated cytotoxicity; chemokine receptor; complement-mediated cytotoxicity; human acute T lymphoblastic leukemia; targeted cancer therapy; therapeutic antibody; xenograft