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.
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