Determination of the potential use of beta-glucan as an adjuvant for monoclonal antibody immunotherapy of cancer

β-Glucan was first reported 40 years ago as a biologic response modifier that stimulated tumor rejection. In vitro studies have shown that β-glucan binding to a lectin domain within complement receptor type 3 (CR3) resulted in the priming of this iC3b (inactivated C3b) receptor for cytotoxicity of iC3b-opsonized tumor cells. In vivo investigations suggested that β-glucan therapy was dependent upon the opsonization of tumor cells with sufficient amounts of iC3b to make them targets for effector cells bearing primed CR3. The β-glucan-primed CR3-dependent cytotoxicity of tumors by leukocytes requires target iC3b on the tumor cells which in previous studies resulted from a natural humoral response to tumor antigens. The hypothesis of the current study is that β-glucan therapy will be most effective when used in combination with a tumor antigen-specific monoclonal antibody (mAb) that enhances iC3b deposition onto tumors.; The current data suggested there was little correlation between the IgG subclass of a mAb and its ability to activate complement or to mediate antibody-dependent cellular cytotoxicity (ADCC). The two anti-G_D2 ganglioside mAb, 3F8 and 14.G2a, mediate efficient ADCC and complement activation in vitro. However, 14.G2a was shown to be more effective than 3F8 in vivo because it was resistant to neutralization by tumor-shed G_D2 antigen. Data also suggested that β-glucans with relatively large size (∼20 kDa) and high CR3-binding affinity might be ideal for tumor therapy. With these β-glucans, the size is large enough to prevent glomerular filtration, and their high affinity for CR3 results in most of the injected dose being taken up rapidly by the liver.; In this study, the EL4 lymphoma was found to be deficient in the expression of CD59 when compared to several other common murine tumor lines. EL4 exhibited a much greater sensitivity to lysis by antibody and mouse complement than did any other tumor line, and EL4 transfection with murine CD59 restored complement resistance. Anti-G_D2 mAb therapy alone of G_D2 + EL4 in C57B1/6 mice could achieve complete remission without need for additional β-glucan therapy. The abnormal complement sensitivity of EL4 is unrepresentative of most tumors, making it an inappropriate target for experimental tumor vaccines, or mAb-enhanced β-glucan therapy trials.; In the treatment of experimental subcutaneous tumors using either MHC class I-negative G_D2+ RMA-S-MUC1 lymphoma in syngeneic C57B1/6 mice or class I-positive Ptas64 mammary tumor in syngeneic Balb/c mice, the combination of β-glucan and antitumor mAb therapy resulted in a significantly greater decrease in tumor weight and a prolonged survival as compared to mAb therapy alone. This suggests that β-glucan-induced CR3 cytotoxicity could serve as an effective adjuvant for therapy with mAb that promote C3 deposition on tumors. The role for tumor-reactive antibodies in facilitating a response to β-glucan, especially in adult syngeneic mice, represents progress towards the development of a novel form of tumor immunotherapy.