DESCRIPTION (provided by applicant): Human sHIgM12 antibody (Ab) activates mouse and human dendritic cells (DCs) by cross-linking the co-stimulatory molecule B7-DC. DCs treated with sHIgM12 Ab do not undergo maturation, distinguishing this activation state from those achieved by engaging the CD40, TNF-, and the toll-like receptors. Antigen-pulsed DCs treated with sHIgM12 induce robust activation of naive T cells. Remarkably, systemic Ab treatment induces an immune-mediated protective response against a lethal challenge of B16 melanoma and promotes resistance against developing tumor nodules in a lung metastasis model. The Ab appears to induce signals directly in DCs, promoting a variety of changes including robust activation of NF-KappaB, increased resistance to apoptosis, and upregulation of cytokines, including IL-12. The current experimental aims are: (1) To determine the mechanism of protection from B16 melanoma induced by treatment of mice with B7-DC cross-linking Ab. We will evaluate the hypothesis that systemic treatment of mice with sHIgM12 Ab leads to the activation of effector T, NK, and B cells, promoting tumor killing mediated by classical effector molecules. (2) To evaluate therapeutic strategies designed to enhance multiple steps in the immune response. Current therapeutic strategies are only partially protective. Experiments are proposed to enhance this novel strategy by recruitment of DCs to the site of tumor growth with GMCSF prior to activation of DCs with B7-DC cross-linking Ab and by promoting the induced effector phase of the immune response by systemic co-stimulation with anti-41BB Ab. (3) To determine the generality of the immune protective effects of sHIgM12 Ab treatment in other tumor models: transplantable myelogenous leukemia WEHI-3B and the spontaneous breast cancer model MMT. As the sHIgM12 Ab activates DCs from multiple mouse strains, as well as human DCs, we seek to determine whether this remarkable therapeutic approach has general applicability to diverse tumor systems in disparate strains of mice.
|Effective start/end date||2/23/04 → 11/30/13|