MONOCLONAL ANTIBODIES IN THE LYMPHATICES FOR DIAGNOSIS AND THERAPY OF TUMORS

我们已经定义了一种新的使用单克隆的方法 诊断和治疗淋巴结肿瘤的抗体： 皮下注射后经淋巴管进入结节 注射。为此建立坚实的药代动力学基础 方法，我们首先研究了针对正常细胞类型的抗体 小鼠淋巴结节。体外结合特性是 结合体内药理参数开发出一种 对交付过程的量化理解使用 SAAM计算机建模系统。有了这样的背景 信息，然后我们演示并分析了特定的吸收 在豚鼠窝肿瘤的淋巴结转移中。该方法 被扩展到包括到达淋巴的内窥镜技术 皮下注射不能接触到的节点组。成象 随后进行了研究，并尝试进行治疗。用于诊断 淋巴结内早期转移的肿瘤，淋巴途径可以 预计会提供更高的灵敏度、更低的背景、更低的 全身毒性，比静脉注射定位更快 路线。它还将最大限度地减少与 存在于正常组织中的抗原。 豚鼠研究的实验设计目前 在临床淋巴结转移检测中的应用 II期恶性黑色素瘤和皮肤T细胞淋巴瘤 (CTCL)。类似的方案已经被批准用于乳房 癌症、霍奇金氏病、小细胞肺癌和非 小细胞肺癌。我们对CTCL的研究已经产生了 迄今获得的最有效的抗原特异性成像 不管用什么技术，人类都是。 体外和动物研究正在继续进行，以优化 临床操作程序和探索的基本功能 免疫系统(见项目#Z01CB08368-2选择性 淋巴管的细胞毒性)。我们的长期目标是 了解单抗和其他单抗的药理学 配体，以开发合理的分子设计标准 生物抗肿瘤药物。

We have defined a new approach to the use of monoclonal antibodies for diagnosis and therapy of tumor in lymph nodes: delivery to the nodes via lymphatic vessels after subcutaneous injection. To establish a firm pharmacokinetic basis for this approach, we first studied antibodies to normal cell types in the mouse lymph node. In vitro binding characteristics were combined with in vivo pharmacological parameters to develop a quantitative understanding of the delivery process using the SAAM computer modeling system. Armed with that background information, we then demonstrated and analyzed specific uptake in lymph node metastases of a guinea pit tumor. The approach was extended to include endoscopic techniques for reaching lymph node groups not accessible by subcutaneous injection. Imaging studies were followed up with attempts at therapy. For diagnosis of early metastatic tumor in the nodes, the lymphatic route can be expected to provide higher sensitivity, lower background, lower systemic toxicity, and faster localization than the intravenous route. It will also minimize the problem of cross-reactivity with antigen present on normal tissues. The experimental design of the guinea pig studies is currently being applied to detection of lymph node metastases in clinical stage II malignant melanoma and cutaneous T-cell lymphoma (CTCL). Similar protocols have been approved for breast carcinoma, Hodgkin's disease, small cell lung carcinoma, and non- small cell lung carcinoma. Our studies of CTCL have produced the most efficient antigen-specific imaging yet achieved in humans by any techniques. In vitro and animal studies are being continued both to optimize the clinical procedures and to explore basic functions of the immune system (see project #Z01CB08368-2 Selective Cytotoxicity in the Lymphatics). Our longer term aim is to understand the pharmacology of monoclonal antibodies and other ligands in order to develop criteria for rational molecular design of biological antitumor agents.