title: Immunotherapy of B-cell non-Hodgkin lymphoma by targeting the chemokine receptor CXCR5 in a preclinical mouse model.
abstract: Bispecific antibodies are promising agents for immunotherapy. Here, we describe a quadroma-based trifunctional bispecific antibody binding the chemokine receptor CXCR5 and the T-cell antigen CD3 that efficiently prevents tumor growth in a mouse B-cell lymphoma model. CXCR5 regulates the tissue homeostasis of mature B cells and is highly expressed on B-cell non-Hodgkin and lymphocyte-predominant Hodgkin lymphoma, as well as on a subset of CD4(+) T cells known as follicular T-helper cells. In vitro, the bispecific CXCR5::CD3 antibody efficiently recruited effector T cells to CXCR5 expressing B cells and induced a co-stimulation-independent activation of CD8(+) and CD4(+) T cells as demonstrated by the de novo expression of CD25 and CD69, and secretion of the cytokines IFN-γ, TNF-α, IL-6 and IL-10 by peripheral blood mononuclear cells. Notably, at low antibody concentrations, CXCR5::CD3 displayed a significantly higher cytotoxic activity against autologous B cells than its parental antibodies or rituximab. In vivo imaging revealed that CXCR5::CD3 and its parental CXCR5 antibody efficiently prevent tumor growth in a xenograft model of B-cell lymphoma in mice and prolong their survival. Taken together, our results identify CXCR5 as a promising target for antibody-based therapies in the treatment of B-cell malignancies.
authors.affiliation: Department of Tumor Genetics and Immunogenetics, Max-Delbrück-Center of Molecular Medicine, MDC, Robert-Roessle-Straße 10, Berlin, Germany.
authors.forename: Hossein
authors.initials: H
authors.lastname: Panjideh
authors.forename: Gerd
authors.initials: G
authors.lastname: Müller
authors.forename: Mathias
authors.initials: M
authors.lastname: Koch
authors.forename: Frank
authors.initials: F
authors.lastname: Wilde
authors.forename: Susanne
authors.initials: S
authors.lastname: Scheu
authors.forename: Gerhard
authors.initials: G
authors.lastname: Moldenhauer
authors.forename: Martin
authors.initials: M
authors.lastname: Lipp
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017252:CD3 Complex / Q000737:chemistry* / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007167:Immunotherapy; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D054380:Receptors, CXCR5 / Q000037:antagonists & inhibitors* / Q000276:immunology; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D018033:Antibodies, Bispecific; D017252:CD3 Complex; D054380:Receptors, CXCR5
keywords: CD3; CXCR5; bispecific antibody; chemokine receptor; immunotherapy; non-Hodgkin lymphoma