Promoting Tumor Immunity by Cross-Linking B7-DC

描述（由申请人提供）：人sHIgM 12抗体（Ab）通过交联共刺激分子B7-DC激活小鼠和人树突状细胞（DC）。用sHIgM 12 Ab处理的DC不经历成熟，将这种活化状态与通过接合CD 40、TNF-α和toll样受体实现的活化状态区分开。用sHIgM 12处理的抗原脉冲的DC诱导幼稚T细胞的稳健活化。值得注意的是，全身性Ab治疗诱导了针对B16黑色素瘤致死性攻击的免疫介导的保护性应答，并促进了对肺转移模型中发展的肿瘤结节的抗性。Ab似乎直接在DC中诱导信号，促进多种变化，包括NF-κ B的稳健活化、对凋亡的抗性增加和细胞因子（包括IL-12）的上调。（1）探讨B7-DC交联抗体对小鼠B16黑色素瘤的保护作用机制。我们将评估这样的假设，即用sHIgM 12 Ab全身治疗小鼠导致效应T、NK和B细胞活化，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个步骤的治疗策略。目前的治疗策略只是部分保护。提出了通过在用B7-DC交联Ab激活DC之前用GMCSF将DC募集到肿瘤生长部位以及通过用抗41 BB Ab全身共刺激促进免疫应答的诱导效应期来增强这种新策略的实验。(3)确定sHIgM 12 Ab治疗在其他肿瘤模型中的免疫保护作用的一般性：可移植性骨髓性白血病WEHI-3B和自发性乳腺癌模型MMT。由于sHIgM 12 Ab激活来自多种小鼠品系的DC以及人DC，我们试图确定这种显著的治疗方法是否对不同品系小鼠中的不同肿瘤系统具有普遍适用性。

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.