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ß-Glucan Functions as an Adjuvant for Monoclonal Antibody Immunotherapy by Recruiting Tumoricidal Granulocytes as Killer Cells

¹ James Graham Brown Cancer Center and
² Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, and
³ Biopolymer Engineering, Inc., Eagan, Minnesota

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. ß-glucan might function as an adjuvant for antitumor mAbs. ß- 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 ß-glucans was limited by levels of natural antibodies and by tumor escape through elimination of antigen-positive cells. Accordingly, it was hypothesized that ß-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 ß-glucan alone, combined treatment with mAb plus ß-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. ß-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 ß-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 ß-glucan.

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