title: Beta-glucan functions as an adjuvant for monoclonal antibody immunotherapy by recruiting tumoricidal granulocytes as killer cells.
abstract: The tumor-killing mechanisms available to monoclonal antibodies (mAbs; e.g., antagonism of growth factor receptors, antibody-dependent cell-mediated cytotoxicity) limit efficacy. Previous studies suggested that i.v. beta-glucan might function as an adjuvant for antitumor mAbs. beta- Glucan had been shown to function via the iC3b-receptor complement receptor 3 (CR3; CD11b/CD18) thereby enhancing leukocyte killing of tumor cells coated with iC3b via naturally occurring antitumor antibodies. Therapy with beta-glucans was limited by levels of natural antibodies and by tumor escape through elimination of antigen-positive cells. Accordingly, it was hypothesized that beta-glucan responses could be improved by combined administration with antitumor mAbs. Five tumor models were explored in BALB/c or C57Bl/6 mice using tumors that expressed either high levels of naturally occurring antigens (e.g., G(D2) ganglioside) or recombinant human MUC1. In comparison with antitumor mAb or beta-glucan alone, combined treatment with mAb plus beta-glucan produced significantly greater tumor regression in all models that included mammary, s.c., and hepatic tumors. Tumor-free survival only occurred in models that incorporated stable expression of the target antigen. beta-Glucan enhancement of the mAb tumoricidal response did not occur in mice deficient in either leukocyte CR3 (CD11b(-/-)) or serum C3, confirming the requirement for CR3 on leukocytes and iC3b on tumors. Granulocytes appeared to be primarily responsible for tumoricidal activity, because beta-glucan therapeutic responses did not occur in granulocyte-depleted mice. These data suggest that the therapeutic efficacy of mAbs known to activate complement (e.g., Herceptin, Rituxan, and Erbitux) could be significantly enhanced if they were combined with beta-glucan.
authors.affiliation: James Graham Brown Cancer Center and. Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky 40202, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Hong
authors.forename: Richard D
authors.initials: RD
authors.lastname: Hansen
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Allendorf
authors.forename: Jarek T
authors.initials: JT
authors.lastname: Baran
authors.forename: Gary R
authors.initials: GR
authors.lastname: Ostroff
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Ross
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D003176:Complement C3 / Q000172:deficiency / Q000276:immunology / Q000378:metabolism; D003179:Complement C3b / Q000276:immunology; D005936:Glucans / Q000276:immunology / Q000494:pharmacology*; D006098:Granulocytes / Q000276:immunology*; D007167:Immunotherapy / Q000379:methods*; D016177:Macrophage-1 Antigen / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D047071:beta-Glucans
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D003176:Complement C3; D005936:Glucans; D016177:Macrophage-1 Antigen; D047071:beta-Glucans; D003179:Complement C3b; C033363:beta-1,3-glucan