Development of an a MC1R selective companion diagnostic imaging probe

The melanocortinreceptorMC Ris over expressed on uveal and cutaneous melanoma cellsbut notin healthy normal tissuesWe have developed a proprietary ligandMTIthat binds to MC R inmelanoma cells with high affinity and specificityThrough our SBIR Phase I contractwedemonstrated that MC R targetedAc DOTA MTIlacks of overt toxicity at single doses thatproduce significant efficacy against uveal and cutaneous melanoma in vivo using xenograft mousemodelsBiodistributionradiodosimetryand PK studies also show rapid blood clearance withpredominant distribution to the targeted tumor or to clearance organs with no organ specificpathologyWe are currently executing a funded Phase II SBIR effort to complete a Phase I doseescalation clinical trial ofAc DOTA MTIin metastatic uveal melanoma patients that willfocus on safety and initial tumor responseLooking aheadit is critical for subsequent clinicalevaluations ofAc DOTA MTIto develop an analogous MC R selective imagingagent to assistwith patient selection and to confirm expression of target after the initial treatment to assist inthe design of multiple dose trialsSuch an agent may eventually serve as a companion diagnosticforAc DOTA MTIor other therapies that target MC RThere is no available Actiniumradioisotope that provides predominant gamma or positron emission that can perfectly mimicAc DOTA MTIbut there are several plus three metal ion radioisotopes that similarly bindDOTA that should perform well as SPECT or PET imaging agentsTheInGa andGa analogsshould mimic the overall PK of the radiotherapeuticHereinwe pursueGa analogs in our initialstudies because its longer radiodecay half life better mimics the expected biological half life ofAcIf our initial Phase I studies support the use ofGa DOTA MTIas an acceptable companion imaging agentthen we can further pursue developmentof theGaDOTA MTIas a SPECT imaging agent or we can consider the development of theGa MTIas aPET imaging agent in follow on Phase II SBIR funded studiesIn additionan imaging probeanalogous toAc DOTA MTImight be used to estimateAc DOTA MTIradiation dose inpatientsThis proposal addresses the initial translational work required to confirmGa DOTA MTIas an MC R imaging agent and potential companion diagnostic to support futureAc DOTA MTItrialsSpecific aims include optimization ofGa DOTA MTIsynthesis andmeasurement ofGa DOTA MTIpharmacokineticsPKtumor to tissue ratiosmechanism of uptakeand dosimetry in preclinical melanoma modelsIf successfulsubsequent funding will be sought tocomplete the translational work and to submit an IND for phaseclinical imaging trialsAc DOTA MTIshows efficacy in metastatic uveal and cutaneous melanoma murine models at dosesthat show no overt toxicity and will soon be studied in patients with metastatic uveal melanomaunder a Phase II SBIR contractThis current application seeks to characterize a potentialcompanion diagnostic imaging agentGa DOTA MTIin preclinical models including mechanismof uptake and dosimetry studies to collect data to support IND submission and subsequent clinicalevaluations