ANALYSIS OF NON-SMALL CELL LUNG CARCINOMA ANTIGENS

总体目标是深入研究肿瘤侵袭的机制。 在生物和分子水平上，并扩大正在进行的研究 单抗定向靶向化疗药物的研究。这 涉及使用单抗开发新的和新的靶向试剂 抗选自沙门氏菌氨基酸序列合成肽的抗体 可识别的肿瘤抗原。为了在以下方面获得基本了解 分子水平上肿瘤抗原结构的重要意义 与肿瘤细胞杀伤有关我们计划定义抗原性和 单抗识别的4万个MR抗原的功能位点 抗体KS1/4。该抗原与此目的高度相关，因为它 是：1)与非小细胞肺癌密切相关，2)存在 在肿瘤细胞表面有极高的数量，3)高度的 一种高效的单抗靶点及单抗药物 结合物体内直接杀伤肺腺癌细胞的实验研究 当在无瘤小鼠中建立时，4)作为 最近启动的使用单抗进行临床试验的目标 抗体-药物结合物。这项提案的基本基本主题是 利用p40抗原的结构产生的试剂将 阐明抗原决定簇与单抗之间的关系 破坏肿瘤细胞的抗体。完整的氨基酸序列将 由氨基酸序列分析和 C-dna的核苷酸序列分析。选定的多肽将是 合成并用作单抗生产的免疫原 抗体。然后将对这些单抗进行测试，以检测其 在动物模型系统中杀死肿瘤细胞的能力。这种用法 单独的单抗，与另一单抗结合并结合到 药物将极大地帮助了解不同的模式 肿瘤杀伤率，因为它们与抗原结构有关。最后，克隆的 P40抗原的基因将被插入到现有的小鼠肿瘤中 为了制作一种更真实的模型来评估其治疗作用 模型系统中的抗人类肿瘤抗原的单抗 免疫能力强的动物。

The overall aim is to study in depth mechanisms involved in tumor invasion at the biological and molecular levels and to extend ongoing studies on monoclonal antibody-directed targeting of chemotherapeutic drugs. This involves the development of new and novel targeting agents using monoclonal antibodies to synthetic peptides selected from the amino acid sequence of a recognized tumor antigen. In order to gain a basic understanding at the molecular level of the significance of tumor antigen structure as it relates to tumor cell killing we plan to define the antigenic and functional sites of the 40,000 Mr antigen recognized by the monoclonal antibody KS1/4. This antigen is highly relevant for this purpose since it is: 1) strongly associated with non-small cell lung carcinoma, 2) present in extremely high quantities on the surface of tumor cells, 3) a highly efficient target for monoclonal antibody and monoclonal antibody-drug conjugates directed in vivo killing of adenocarcinoma of the lung cells when established in athymic mice and 4) the antigen which serves as the target for the recently initiated clinical trial using monoclonal antibody-drug conjugates. The basic underlying theme of this proposal is to utilize the structure of the p40 antigen to generate reagents that will clarify the relationship between antigenic determinants in and monoclonal antibodies that destroy tumor cells. The complete amino acid sequence will be determined by a combination of amino acid sequence analysis and nucleotide sequence analysis of c-DNA. Selected peptides will be synthesized and used as immunogens for the production of monoclonal antibodies. These monoclonal antibodies will then be tested for their ability to kill tumor cells in an animal model system. Such use of monoclonal antibodies alone, in combination with another and conjugated to drugs will greatly aid gaining an understanding of the different modalities of tumor killing as they relate to antigen structure. Finally, the cloned gene of the p40 antigen will be inserted into an existing mouse tumor in order to produce a more realistic model to assess the therapeutic role of monoclonal antibodies to human tumor antigens in a model system involving immunologically competent animals.