Developing a commercial charge detection mass spectrometer for MDa to GDa mass measurements

Project Summary This proposal describes key steps towards generating the first commercial charge detection mass spectrometerCharge detection mass spectrometryCDMSis an emerging technology that can measure the masses of large heterogeneous biopharmaceuticals and nanoparticlesCurrent commercial mass spectrometers measure the mass to charge ratiom zof ensembles of ions and require charge assignment to determine massDue to overlapping charge states this approach breaks down for masses above around a megadaltonMDaeven under favorable conditionsCDMS overcomes this limitation by simultaneously measuring the m z and the z of individual ionsm z and z are then multiplied to give m for each ionBy extending the upper mass limit by several orders of magnitudeCDMS has disruptive potential for the characterization and discovery of new therapeutics and disease markers in the same way current commercial mass spectrometers have had for small moleculesHoweverCDMS is currently only available in a few academic laboratoriesTo make it more widely available we will install a CDMS detector on a commercial quadrupole time of flightQ TOFmass spectrometerThe CDMS detector will use technology developed in the Jarrold lab at Indiana Universityand employed there for a number of yearsThe modification will be performed in a way that retains all the functionalities of the Q TOF for light ions while adding the capability to analyze high mass ions by CDMSA suite of molecules that can be detected by both conventional time of flight MS and CDMS will be used to calibrate the CDMS m z and z measurements and evaluate the mass resolutionThe high mass performance of the hybrid Q CDMS TOF instrument will be evaluated with a number of high mass speciesMDathat have previously been measured by CDMSCommercial instruments are not optimized to transmit very high mass ions so modifications will be made to the Q TOF to improve the transmission efficiencyThis new Q CDMS TOF instrument will extend MS far beyond the mass range of current commercial instrumentsenabling measurements for entire new classes of biologicse gvaccines and gene therapy productsnanoparticlessuch as liposomes and solid lipid hybridslarge biomarkerssuch as lipoproteins and exosomesand many more yet to be identifiedBecause CDMS can analyze very heterogeneous samplesthere are potential applications in diagnostic tests and in process control and monitoring during pharmaceutical formulationsSeven pharmaceutical companies have approached us with interest in purchasing CDMS instrumentstwo of these in the last monthMost of these contacts have led to research agreements and or service contracts in order to characterize large molecule targetsWe expect the interest from pharmaceutical companies to continue to grow as the measurements become more main streamThe development of a commercial Q CDMS TOF instrument for robusthigh throughput measurements is the key to meeting this growing need Project Narrative Charge detection mass spectrometryCDMSallows accurate molecular weights to be measured for samplessuch as vaccinesliposomesgene therapy vectorsand lipoproteinsthat are well beyond the mass range of conventional mass spectrometersThis proposal outlines a plan to integrate CDMS into a commercial MS platforma first step in commercializing CDMSThe availability of a commercial CDMS instrument will have wide ranging impact on human healthfrom better characterization of biopharmaceuticals to the development of new diagnostics and therapeutic targets