Development of a Companion Diagnostic Assay for Detection of ADAM8-Positive Cancers

Triple negative breast cancersTNBCsaccount yearly forof all breast cancer deathsThe current Standard of CareSoCsurgeryradiation and chemotherapyCTis not curativeMore effectivetargeted treatments are urgently neededRecentlywe identified the cell surface protein ADAMas a critical driver of TNBC tumor growth and metastasis via its MetalloproteaseMPand DisintegrinDIdomainsrespectivelyand showed that treatment with an ADAMdual MP DI antagonist monoclonal antibodymAbreduces TNBC primary growth and metastases in miceThuswe proposed that ADAMdual antagonist antibody therapy will become a new component of care for TNBC and founded Adecto PharmaceuticalsIncAdectoto bring this therapy to patientsWith Phase I STTR fundingwe generated a panel of highly specific anti human ADAMdual antagonist mAbstermed ADPsand identifiedtop inhibitorsADPand ADPthat reduced pre existing primary tumor growth and metastasisand improved survival as monotherapiesAddition of ADPto the SoC CT AbraxaneABXenhanced ABX mediated tumor inhibition and disease free and overall survivalThusADAMantibody combination therapy could dramatically improve patient outcomeAdecto was recently awarded a Phase II SBIR grant to continued development of this therapyOf notehigh ADAMlevels correlate with poor patient prognosisand are seen onof primary TNBCs andof all breast cancer metastasesThusto identify patients who can benefit from ADAMtargeted therapya diagnostic assay will be neededAs there is currently no FDA approved product for diagnosis of ADAMcancershere we propose to begin development using immunohistochemistryIHCof formalin fixed paraffin embeddedFFPEpatient biopsiesAs this procedure requires antibodies that recognize ADAMprotein under fixed conditions following retrieval from paraffin embeddingwe propose first to identify an IHC appropriateclinical gradeADAMmAb for development using our panel of ADPs as a starting pointTwelve of theADPs detected ADAMon the surface of fixed cells in FACS analysisADPandshowed particularly strong binding and were selected for further studiesPreliminary IHC with FFPE pellets of HEKcells expressing transfected human ADAMHEK Avs empty vectorHEK EVsupport continued assessment of these mAbsHereour milestones are toselect a lead ADP for IHC based on both efficacyusing HEK EV vs HEK Aand specificityusing FFPE samples of HEK cells expressing related proteins ADAMordevelop an IHC scoring system for staining standardization using a control cell microarrayCCMcontaining FFPE samples of breast cancer cell lines with a gradient of ADAMlevels and confirm the range with Patient Derived Xenograft FFPE and tissue samplesvalidate our lead ADP and CCM using TNBC primary patient FFPE samplesIdentification of an ADAMIHC antibody with a strong data package will help us attract Phase II funding and a partner for full development of a diagnostic product for selection of patients who can benefit from ADAMtargeted therapy The ADAMcell surface protein has been identified as a critical driver of tumor growth and spread in triple negative breast cancerTNBCa highly aggressive disease which accounts for more thanof theyearly breast cancer deaths worldwideA novel antibody based ADAMtargeted therapy which inhibits the two extracellular domains of this protein responsible for its cancer promoting functions is under development and has the potential to revolutionize TNBC treatment by significantly enhancing patient survivalHerewe propose to identify an anti ADAMantibody for IHC based detection of ADAMexpressing cancers with optimal staining conditionscontrol panelscoring system and early patient sample validationas the first step in the development of an FDA approvable diagnostic assay that will enable selection of patients who can benefit from this important new personalized therapy