EVALUATE LAG3 AND OTHER IMMUNE MODULATORS

评估 LAG3 和其他免疫调节剂

• 批准号: 7612666
• 负责人: DREW M. PARDOLL
• 金额: $ 23.2万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7612666
• 关键词: Agonist; Antibodies; Antigens; B7-DC antigen; Be++ element; Beryllium; Binding; Binding Sites; Blocking Antibodies; Cancer Biology; Cancer Immunology Science; Cancer Model; Cell surface; Cells; Dendritic Cells; Development; Endopeptidases; Family member; Genes; Human; Immune; Immune response; Immunity; In Vitro; Interleukin-2; Laboratories; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Modeling; Monoclonal Antibodies; Mus; Normal tissue morphology; Pancreas; Peptide Hydrolases; Reagent; Recombinants; Serum; System; T-Lymphocyte; Testing; Transgenic Model; Tumor Antigens; Vaccines; base; cancer immunology function; functional genomics; gene discovery; in vivo; mesothelin; mouse model; mutant; receptor; response; selective expression; tumor

Applications of functional genomics to the identification of relevant human tumor antigens such as mesothelin in pancreatic and ovarian cancer provide the basis for antigen specific vaccines. However, the ultimate potency of vaccine induced antitumor immune responses is limited by preexisting tolerance, even when the targeted tumor antigen displays limited expression by normal tissues. We and others have demonstrated that amplification of immune responses in the setting of preexisting tolerance can be achieved by a) increasing costimulation and b) inhibiting the activity of Treg cells. Therefore, the major aim of this NCDDG element is to develop a costimulatory agonist and a Treg antagonist, based on gene discovery efforts within our laboratory, which will be used to amplify mesothelin-based vaccines. Recently, we discovered a new B7 family member, termed B7-DC, that is selectively expressed by dendritic cells. B7-DC can act as a strong costimulator for Th1 responses in synergy with B7.1 or B7.2. This costimulatory activity is independent of PD-1, an inhibitory receptor to which B7-DC can bind. Aim#1 of this section will be the development and characterization of both murine and human mutant B7-DC-Fc molecules (termed B7-DC*-Fc) that have lost PD-1 binding activity but retain costimulatory activity. As part of a gene profiling project to identify Treg specific genes, we identified LAG-3 as a Treg specific cell surface molecule. In the mouse, both natural and induced Treg express increased levels of LAG-3 and antibodies to murine LAG-3 block Treg activity both in vivo and in vitro. Anti-LAG-3 monoclonal antibodies will be developed as Treg antagonists. Based on our findings that anti-LAG-3 antibodies block Treg activity in murine systems, together with the finding that tolerant T cells in various murine tumor systems express increased LAG-3, Aim#2 of this section will be to produce both murine and human anti-LAG-3 antibodies and test them for their ability to inhibit Treg cells. These agents will be combined with mesothelin-based vaccines in Sections 1 and 2 of the NCDDG.

功能基因组学在鉴定胰腺和卵巢癌中相关的人肿瘤抗原（例如间皮素）中的应用为抗原特异性疫苗提供了基础。然而，即使靶向肿瘤抗原显示出正常组织有限的表达，疫苗诱导的抗肿瘤免疫反应的最终效力也受到耐受性的限制。我们和其他人已经证明，可以通过a）增加共刺激和b）抑制Treg细胞活性来实现免疫反应的扩增。因此，该NCDDG元素的主要目的是基于我们实验室内的基因发现工作，开发一种共刺激激动剂和TREG拮抗剂，该工作将用于扩增基于间皮素的疫苗。最近，我们发现了一个新的B7家族成员，称为B7-DC，该成员由树突状细胞有选择地表达。 B7-DC可以充当与B7.1或B7.2协同作用的TH1响应的强大共矩阵。这 共刺激活性与PD-1无关，PD-1是B7-DC可以结合的抑制受体。本节的目标＃1将是鼠和人类突变体B7-DC-FC分子（称为B7-DC*-FC）的发展和表征，这些分子失去了PD-1结合活性，但保留了costimulation活性。作为鉴定特雷格特异基因的基因分析项目的一部分，我们将lag-3鉴定为特雷格特异性细胞表面分子。在鼠标中，两者都自然 并诱导Treg Express在体内和体外诱导的lag-3和抗体抗体的水平增加。抗LAG-3单克隆抗体将作为Treg拮抗剂开发。基于我们的发现，抗LAG-3抗体阻止了鼠系统中的Treg活性，以及​​发现各种鼠肿瘤系统中的耐受性T细胞表达的lag-3增加了lag-3，本节的AIM＃2将是生产鼠和人类抗LAG-3 抗体并测试其抑制Treg细胞的能力。这些药物将与NCDDG第1节和第2节中的间皮基疫苗结合使用。