TARGETING THE VASCULATURE OF SOLID TUMORS

针对实体瘤的脉管系统

• 批准号: 2870261
• 负责人: PHILIP E THORPE
• 金额: $ 20.28万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2870261
• 关键词: SDS polyacrylamide gel electrophoresis; biomarker; blood chemistry; drug design /synthesis /production; drug screening /evaluation; enzyme linked immunosorbent assay; gas chromatography; guinea pigs; hepatocellular carcinoma; hybridomas; immunoconjugates; immunocytochemistry; immunoglobulin G; immunoprecipitation; immunotoxicity; laboratory mouse; monoclonal antibody; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; nonsmall cell lung cancer; pharmacokinetics; receptor binding; receptor expression; tissue /cell culture; vascular endothelial growth factors; western blottings

DESCRIPTION: (Applicant's Abstract) The goal of this application is to create immunoconjugates that home to the vasculature of solid tumors, coagulate the tumor's blood supply and induce tumor infarction. The key advantage of this approach over direct tumor cell targeting is that the vascular endothelial cells of the tumor are freely accessible through the blood whereas the tumor cells are relatively inaccessible. Also, endothelial cells are normal cells making the outgrowth of resistant mutants unlikely, and are similar in different tumors, making it feasible to develop a single reagent for treating numerous types of cancer. The applicant previously established "proof of principle" by inducing major tumor regressions in mice bearing large solid tumors with immunoconjugates prepared from antibodies that recognize an experimentally-induced tumor endothelial cell marker (MHC Class II). The effectors were ricin A-chain, which kills the tumor endothelial cells and induces platelet adhesion on the injured vessels, or a genetically engineered form of the coagulation initiating protein tissue factor, which directly induces thrombotic occlusion of the vessels. In this application, the applicant will synthesize vascular targeting agents that recognize the naturally occurring tumor endothelial cell marker, vascular endothelial cell growth factor (VEGF). VEGF is present in the receptors on tumor endothelial cells but not in those on endothelial cells in normal tissues and, hence, non-blocking antibodies to VEGF home selectively to tumor vessels in vivo. Monoclonal antibodies to human VEGF will be raised; their ability to localize to vessels in solid tumors in mice and guinea pigs will be confirmed; toxin-containing immunotoxins and tissue factor-containing "coaguligands" will be synthesized; and the pharmacokinetics, toxicity and anti-tumor activity of the drugs in murine and guinea pig tumor models will be determined. These studies will pave the way to clinical trials of anti-VEGF vascular targeting agents in patients with solid tumors.

描述：（申请人的摘要）此申请的目的是 创建免疫共轭物，是实体瘤的脉管系统的家园 凝结肿瘤的血液供应并诱导肿瘤梗塞。 钥匙 这种方法比直接肿瘤细胞的靶向优势是 肿瘤的血管内皮细胞可以通过 血液，而肿瘤细胞相对无法访问。 还， 内皮细胞是正常细胞，使抗性突变体的生长产生 不太可能，在不同的肿瘤中相似，使发展可行 一种用于治疗多种类型癌症的试剂。 申请人 先前通过诱导重大肿瘤建立的“原理证明” 带有免疫缀合物的大型实体瘤的小鼠的回归 从识别实验诱导的肿瘤的抗体中制备 内皮细胞标记（MHC II类）。 效应子是ricin a链， 杀死肿瘤内皮细胞并诱导血小板粘附 受伤的血管或凝结的基因工程形式 启动蛋白质组织因子，直接诱导血栓形成 容器的阻塞。 在此申请中，申请人将 合成识别天然发生的血管靶向剂 肿瘤内皮细胞标记，血管内皮细胞生长因子 （VEGF）。 VEGF存在于肿瘤内皮细胞的受体中，但不存在 在正常组织中的内皮细胞上，因此无障碍物 在体内选择性地对肿瘤血管有选择性地回家的抗体。 单克隆 将提出对人VEGF的抗体；他们本地化的能力 将确认小鼠和豚鼠实体瘤的血管； 含毒素的免疫毒素和含有组织因子的“凝结物” 将合成；以及药代动力学，毒性和抗肿瘤 药物在鼠和豚鼠肿瘤模型中的活性将是 决定。 这些研究将为抗VEGF的临床试验铺平道路 实体瘤患者的血管靶向剂。