ANALYSIS OF NON-SMALL CELL LUNG CARCINOMA ANTIGENS

总体目标是深入研究肿瘤侵袭的机制 在生物学和分子水平上， 单克隆抗体导向的化疗药物靶向。 这 涉及使用单克隆抗体开发新的和新颖的靶向剂， 针对选自以下氨基酸序列的合成肽的抗体： 识别肿瘤抗原。 为了获得基本的了解， 肿瘤抗原结构的分子水平的意义，因为它 与肿瘤细胞杀伤有关，我们计划定义抗原， 单克隆抗体识别的40，000 Mr抗原的功能位点 抗体KS 1/4。 该抗原与此目的高度相关，因为它 1）与非小细胞肺癌密切相关，2）存在 在肿瘤细胞表面的数量非常高，3）高度 单克隆抗体和单克隆抗体-药物的有效靶点 直接体内杀死肺腺癌细胞的缀合物 当在无胸腺小鼠中建立时，和4）用作 最近启动的使用单克隆抗体的临床试验的目标 抗体-药物缀合物。 该提案的基本主题是 利用p40抗原的结构来产生试剂， 阐明抗原决定簇与单克隆抗体之间的关系 破坏肿瘤细胞的抗体。 完整的氨基酸序列将 可以通过氨基酸序列分析和 c-DNA的核苷酸序列分析。 选定的肽将是 合成并用作生产单克隆抗体的免疫原 抗体的 然后将测试这些单克隆抗体的 在动物模型系统中杀死肿瘤细胞的能力。 的这种使用 单独的单克隆抗体，与另一种单克隆抗体组合并缀合至 药物将大大有助于了解不同的模式， 因为它们与抗原结构有关。 最后，克隆 p40抗原的基因将被插入现有的小鼠肿瘤中， 为了产生一个更现实的模型来评估治疗作用， 在涉及以下的模型系统中的针对人肿瘤抗原的单克隆抗体 有免疫能力的动物。

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.