Beta-glucan functions as an adjuvant for monoclonal antibody immunotherapy by recruiting tumoricidal granulocytes as killer cells

Cancer Res. 2003 Dec 15;63(24):9023-31.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma / immunology
  • Adenocarcinoma / therapy
  • Adjuvants, Immunologic / pharmacology*
  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology*
  • Complement C3 / deficiency
  • Complement C3 / immunology
  • Complement C3 / metabolism
  • Complement C3b / immunology
  • Glucans / immunology
  • Glucans / pharmacology*
  • Granulocytes / immunology*
  • Immunotherapy / methods*
  • Macrophage-1 Antigen / immunology
  • Mammary Neoplasms, Experimental / immunology
  • Mammary Neoplasms, Experimental / therapy
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • beta-Glucans*

Substances

  • Adjuvants, Immunologic
  • Antibodies, Monoclonal
  • Complement C3
  • Glucans
  • Macrophage-1 Antigen
  • beta-Glucans
  • Complement C3b
  • beta-1,3-glucan