Promoting Tumor Immunity by Cross-Linking B7-DC

描述(申请人提供)：人类sHIgM12抗体(Ab)通过交联共刺激分子B7-DC来激活小鼠和人类树突状细胞(DC)。经sHIgM12抗体处理的DC不经历成熟，这一激活状态有别于通过结合CD40、肿瘤坏死因子-1和Toll样受体实现的激活状态。经sHIgM12处理的抗原致敏的DC可诱导初始T细胞的强烈激活。值得注意的是，全身性抗体治疗诱导了针对B16黑色素瘤致死性攻击的免疫介导性保护性反应，并在肺转移模型中促进了对肿瘤结节形成的抵抗。抗体似乎直接在DC中诱导信号，促进各种变化，包括强大的核因子-kappaB的激活，增强对凋亡的抵抗力，以及上调包括IL-12在内的细胞因子。目前的实验目的是：(1)探讨B7-DC交联型抗体对小鼠B16黑色素瘤的保护作用机制。我们将评估sHIgM12抗体全身治疗导致效应T、NK和B细胞激活的假说，促进经典效应分子介导的肿瘤杀伤。(2)评估旨在增强免疫反应多步骤的治疗策略。目前的治疗策略只能起到部分保护作用。在用B7-DC交联型抗体激活DC之前，用GMCSF将DC募集到肿瘤生长部位，并通过与抗41BB抗体系统共刺激促进免疫反应的诱导效应相，实验被提出以加强这一新策略。(3)探讨sHIgM12单抗在可移植性髓系白血病WEHI-3B和自发性乳腺癌模型MMT中免疫保护作用的共性。由于sHIgM12抗体可激活多个小鼠品系的DC以及人类DC，我们试图确定这种非凡的治疗方法是否适用于不同品系小鼠的不同肿瘤系统。

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.