Novel carcinoma-specific monoclonal antibodies for therapies and diagnostics

Problems that cause significant negative impacts on cancer patientsandaposquality of life and on their survival include current therapies that lead to unwanted side effects due to their action on normal cellsFurthermoreinvading carcinoma cells can be resistant to therapies due to the migration proliferation dichotomyMonoclonal antibodyMabtherapiessuch as those against EGFVEGFc Met and their respective receptorscan target invading carcinoma cellsHoweverthese molecular targets are on normal cellsWhile there are cancer cell specific mutations that can be targetedthese mutations do not cause the majority of solid tumor cancersTo address these problems our goal is to develop the first Migration Inducting GeneMigMabs using our proprietary knowledge of the unusual programmed ribosomal shift site that is located at two stop codons nine amino acids into the translation of MigproteinThese stop codons are read through during MigtranslationPrior research shows that our polyclonal antibody to Migsignificantly inhibits cancer cell invasionData suggest that Migprotein is an important Mab target because cell surface Migprotein expression leads to metastasis by causing cancer cells to aggressively invadeHowevera MigMab therapy does not existMigprotein is found inof malignant cases of carcinoma and melanoma examinedExhaustive studies characterizing Migexpression show that no normal or inflammatory cells express Migpost gestationMigprotein specifically localizes to cancer cells ofprimary tumorsinvading cancer cellsabnormal vessels of tumorsblood of untreated cancer patientsand metastatic sitesindicating a broad range of Mab targeting opportunitiesThereforea Migspecific Mab is needed for future clinical useOur approach to developing and testing MigMabs will focus on our knowledge of Migprotein as well as our quantitative functional assays and endometrial carcinoma nude mouse model of metastasis to lymph nodesLNsOur goal in Phase I is to develop Migfunction inhibiting MabsThereforeour aims are toGenerate cell lines expressing Mabs to four proprietary Migpeptidesincluding the peptide immunogenic in rabbitand determine specificity to each peptideQuantify the MigMab effect on Migfunction of carcinoma cell invasion in vitro using our transwell invasion assay that is predictive of metastatic potential in vivoandQuantify MigMab effects on metastasis to LNs in our xenograft mouse model of endometrial carcinomaECexperimental metastasisIn the future Phase II proposalMigMabs will be humanized and tested for additional mechanisms of action to enable filing an INDOur development of the MigMab therapy will be unique because one does not exist andlike Migexpressionit will be highly carcinoma specificImportantlyMigMab therapies may overcome some current drug resistance during therapyThe antigen binding region of this Mab could also be used to make other promising cancer therapies such as chimeric antigen receptor T cells and anti immune suppression more specific to carcinoma cells Cancer specific Migration inducting geneMigprotein promotes metastasis by activating several essential pathways in this lethal aspect of cancerMigpolyclonal antibody is effective to inhibit these functionshoweverMigmonoclonal antibodiesproposed in this Phase I projectare required for development into therapiesA novelbroadly carcinoma specific monoclonal antibody therapy capable of simultaneously targeting several metastasis promoting pathwaysmultiple mechanisms of drug resistance as well as negative side effects of current therapies should have a major impact on future cancer therapies and improve patient quality of life