AnnotatedSomaLogicandThird-partyPublications
Thispartiallistofpeer-reviewedpublicationsincludesmanuscriptsdescribing
applicationsofthetechnology(below)aswellasbasicresearchonthetechnology
itself(startingonp.21).
Note:LinksareprovidedtotheactualmanuscriptifitisOpenAccess,ortothe
PubMedentryifarticleaccessrequiresasubscriptiontothatjournal(asnotedin
eachentrybelow).
I.SOMAscan®Assay/SOMAmer®ReagentApplications
Basic,preclinicalandclinicalresearch
____________________________________________________________________________________________
AsaiAetal.(2017)Paracrinesignalsregulatehumanliverorganoidmaturationfrom
inducedpluripotentstemcells.Development144:1056-1064.
http://dev.biologists.org/content/144/6/1056.long
Humaninducedpluripotentstemcells(iPSCs)candifferentiateandself-organizeintoaliver
“organoid”inaPetridish.InvestigatorsatCincinnatiChildren’sHospitalMedicalCenterfound
thatathree-dimensionalarchitectureonlyformswheniPSC-derivedlivercells(HE-iPSCs)are
indirectcontactwithmesenchymalstemcells(MSCs)andhumanumbilicalveinendothelial
cells(HUVECs).However,maturationofHE-iPSCsfromfetaltoadult-likehepatocytescanbe
inducedevenwhenthecellsarekeptseparatebutallowedtoexchangesolublefactors.To
identifythesesignalingmolecules,theSOMAscanassaywasusedtoanalyzethesupernatants
ofHE-iPSCsco-culturedwitheitherMSCs,HUVECsorboth.Thelevelsof228proteinschanged
significantly(≥three-fold)whencomparedtoHE-iPSCsculturedalone,anddifferentproteins
weresecreteddependingonthecombinationofcellsthatwerepresent.Theseresultswillhelp
furtherstudiestodissectthemechanismsbehindliverorganogenesisandregeneration.
_____
TrauschJJetal.(2017)DevelopmentandcharacterizationofanHPVType-16specific
modifiedDNAaptamerfortheimprovementofpotencyassays.AnalChem.,Epubaheadof
print.(Subscriptionrequired).
https://www.ncbi.nlm.nih.gov/pubmed/28233502
Robustpotencytestsensurethatvaccinesreleasedtothepublicremainsafeandeffective.
Mostapprovedpotencyassaysrelyonantibodyreagents,whichhavemanydrawbacks(e.g.
time-consumingdiscoveryprocess,limitedshelflife,batch-to-batchvariability,etc.).Toget
aroundtheseproblems,researchersatMercksubstitutedanantibodywithanaptamerina
humanpapillomavirus(HPV)potencyassay.TheyworkedwithSomaLogictocreateacustom
SOMAmerreagent(namedHPV-07)thatbindstightlytoHPV16,ahigh-risktypeforcervical
cancer.HPV-07wasdesignedtobindselectivelytoHPV16insamplesthatcontainmanyother
HPVtypes.CompetitionexperimentsrevealedthatHPV-07bindstothesameepitopeasawellcharacterizedHPV16antibody,andwhenusedinanELISAformat,HPV-07displayedhigh
accuracy,precisionandawidelinearrange.TheresearchersthenfunctionalizedHPV-07to
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developasimple“mixandread”assaythatwasfasterandcheapertorunthananELISA.They
notethatthepropertiesofSOMAmerscouldbeexploitedfurthertocreateamultiplexedassay
thatmeasuresthepotencyofallantigensinamultivalentvaccinesimultaneously.
_____
WoodGCetal.(2017)Amulti-componentclassifierfornonalcoholicfattyliverdisease
(NAFLD)basedongenomic,proteomic,andphenomicdatadomains.SciReports7:43238.
http://www.nature.com/articles/srep43238
Approximately25%ofAmericanshavenon-alcoholicfattyliverdisease(NAFLD),adisorderin
whichexcessfataccumulatesintheliver.NAFLDisoftenassociatedwithobesityandcan
progresstomoreseriouschronicconditionsincludingliverinflammation,fibrosisandcirrhosis.
ManypeoplewithNAFLDareasymptomatic,andcommonlyusedtestsofliverfunctionlack
thespecificityandsensitivitytocheckforNAFLD.AsobesityratesintheU.S.continuetorise,
thereisanurgentpublichealthneedforclinicalbiomarkersofNAFLD.Inthisstudy,
researchersattheGeisingerObesityResearchInstituteinPennsylvaniaandNationalJewish
HealthinColoradousedgenomic,phenomicandproteomicdatatodevelopanalgorithmthat
predictsNAFLDinanextremelyobesepopulation.Thedataincludedasinglenucleotide
polymorphisminthePNPLA3genethatislinkedtoNAFLDsusceptibility,16clinicalvariables
thathadbeenshownpreviouslytocorrelatewithNAFLD,and8serumproteinbiomarkersof
NAFLDidentifiedbySOMAscanassayanalysis.Theresultsrepresentanimportantsteptoward
developingaminimally-invasivetestforNAFLDdiagnosisandprognosis.
_____
GuiraudSetal.(2017)IdentificationofserumproteinbiomarkersforutrophinbasedDMD
therapy.SciReports7:43697.
http://www.nature.com/articles/srep43697
Duchennemusculardystrophy(DMD)isafataldegenerativemuscledisorderthatiscausedby
mutationsinthegenethatencodes“dystrophin,”acriticalmusclestructureprotein.Utrophin
isaproteinwithhighsimilaritytodystrophin(80%homology)thatcancompensateforlossof
dystrophinfunction.Overexpressionofutrophinpreventsdiseasepathogenesisinamouse
modelofDMDandisofgreatinterestasapotentialtherapeuticstrategyinhumans.
ResearchersattheUniversityofOxfordperformedtheSOMAscanassayonbloodserum
samplesfromwildtype,dystrophin-null(mdx)andutrophin-overexpressingmdx(Fiona)mice.
Theyidentified83proteinsthatdifferedsignificantlyinconcentration(>two-fold)between
mdxandwildtypemice,34ofwhichwerefullyrestoredtonormallevelsinFionamice.These
proteinsrepresentpossiblebiomarkersthat,ifvalidatedinhumans,couldbeusedtomonitor
diseaseprogressionandresponsetotherapeutics.
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SuhreKetal.(2017)Connectinggeneticrisktodiseaseendpointsthroughthehuman
bloodplasmaproteome.NatCommun.8:14357.
http://www.nature.com/articles/ncomms14357
ResearchersattheWeillCornellmedicalcollegeinQatarusedtheSOMAscanassayto
investigatetheimpactofcommongenevariantsonproteinlevelsinhumanplasma.Using
samplesfromaGermancohort,theyidentified539singlenucleotidepolymorphism-protein
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associationsandreplicatedoverhalfoftheresultsinanArabandAsiancohort.The
associationsoverlapwith57geneticrisklocifor42differentdiseaseendpoints.Interestingly,
manyoftheproteinsaremodulatedbyvariationsthatoccurondifferentchromosomes.This
studydemonstrateshowproteomicscanhelptiegenomicobservationstoactualchangesin
physiologyandpathology.Theauthorsanticipatethatfurtherminingoftheirdatawill
provideinsightsintodisease-relatedbiologicalpathwaysandtherapeuticinterventions.
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EscolanoJMetal.(2017)SelectionofaptamerstoNeisseriameningitidisandStreptococcus
pneumoniaesurfacespecificproteinsandaffinityassayusingthinfilmAlNresonators.
SensorsandActuatorsB:Chemical246:591–596.(Subscriptionrequired).
http://www.sciencedirect.com/science/article/pii/S0925400517303258
Bacterialmeningitisisafrighteningillness—victimscandiewithinafewhoursandsurvivors
canbeleftwithsevereafflictionssuchasbraindamageorhearingloss.Differentkindsof
bacteriacancausemeningitis,ofwhichNeisseriameningitidisandStreptococcus
pneumoniaearethemostcommon.ResearchersinMadridgeneratedpolyclonalSOMAmersto
twobacterialsurface-expressedproteins,PavAfromS.pneumoniaeandFHbpfromN.
meningitidisanddemonstratedspecificbindingoftheSOMAmerstotheirtargetproteins.This
workrepresentsanimportantfirststeptowardscreatingabiosensorforrapiddetectionof
bacterialmeningitis.
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VandenBroekTJetal.(2017)Theimpactofmicronutrientstatusonhealth:correlation
networkanalysistounderstandtheroleofmicronutrientsinmetabolic-inflammatory
processesregulatinghomeostasisandphenotypicflexibility.Genes&Nutrition12:5.
https://genesandnutrition.biomedcentral.com/articles/10.1186/s12263-017-0553-7
Healthcanbedefinedasthebody’sabilitytoadapttoenvironmentalchanges,suchas
infection,stressorexercise.ResearchersintheNetherlandsandSwitzerlandusedthis
definitiontostudytherolesoffat-solublemicronutrientsinmaintainingnormalphysiological
processes.PlasmaconcentrationsofvitaminsA,D3&Eandfourcarotenoidsweremeasured
for36overweightorobesemalesafterovernightfastingandaftereatingahighfatshake.A
proteomicanalysisusingtheSOMAscanassaywasconductedinparallel,andchangesin
proteinlevelswerecorrelatedwithchangesinmicronutrientlevels.Thecorrelationanalysis
afterthenutritionalchallengewasparticularlyinterestingasitsuggestedthatcertain
micronutrients(α-carotene,avitaminAprecursor;andγ-tocopherol,aformofvitaminE)are
especiallyimportantforhelpingthebodyrespondtooxidativeandinflammatorystresses.This
approachwillbeusefulforquantifyingtheeffectsofdietonhealth.
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DiNarzoAFetal.(2017)High-throughputcharacterizationofbloodserumproteomicsof
IBDpatientswithrespecttoagingandgeneticfactors.PLoSGenet.13(1):e1006565.
http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1006565
Inthisarticle,scientistsattheIcahnSchoolofMedicineatMt.Sinaianalyzedthebloodserum
ofpatientswithinflammatoryboweldisease(IBD)—ulcerativecolitisandCrohn’sdisease
(CD)—aswellashealthycontrols.TheydescribeusingtheSOMAscanassaytoidentifyserum
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proteinsthatcorrelatewithCDandwithaging.WithinaCDcohort,theyfound41proteins
thatassociatedwithpreviouslyidentifiedgeneloci,includingawell-knownIBDsusceptibility
locus.ThisstudyillustratesthevalueoftheSOMAscanassayininterpretinggenome-wide
associationstudy(GWAS)resultsandingaininginsightintothemoleculareventsthatcause
IBD.
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SasayamaDetal.(2017)Genome-widequantitativetraitlocimappingofthe
humancerebrospinalfluidproteome.HumMolGenet.26(1):44-51.(Subscription
required).
https://academic.oup.com/hmg/articleabstract/doi/10.1093/hmg/ddw366/2595397/Gen
ome-wide-quantitative-trait-loci-mapping-of-the?redirectedFrom=fulltext
Measuringanalytesincerebrospinalfluid(CSF)canbeusefulfordiagnosingdiseasesofthe
centralnervoussystem.ResearchersinJapanconductedagenome-widestudyofsingle
nucleotidepolymorphisms(SNPs)intheCSFof133physicallyhealthyindividualsandusedthe
SOMAscanassaytolookforcorrelatedchangesinproteinconcentrations.Theyidentifiedover
400SNP-proteinpairs,ofwhich28hadbeenshownpreviouslytoassociatewithspecifictraits
ordiseases.Interestingly,manyoftheproteinassociationsappeartobeuniquetoCSF(i.e.,
theyhadnotbeenpreviouslyidentifiedfromblood).Thissuggeststhatgenevariants
differentiallycontrolproteinlevelsinthecentralvs.peripheralnervoussystem.Theseresults
shouldaidfutureeffortstounderstandbrainbiochemistryandtodiscovernewbiomarkersfor
neurologicaldiseases.
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JungYJetal.(2017)Developmentofaproteinbiomarkerpaneltodetectnon-small-celllung
cancerinKorea.ClinicalLungCancer18:e99-e107.(Subscriptionrequired).
http://www.sciencedirect.com/science/article/pii/S1525730416302388
Lungcanceristhemostcommonandmostdeadlycancerintheworld.Earlydetectionand
treatmentgreatlyimproveschancesofsurvival,butthiscanbedifficultsincepeoplewithearly
stagelungcancerareoftenasymptomatic.Theonlycurrentlyrecommendedscreeningtestfor
lungcancerisalow-doseCTscan,whichhasahighfalsepositiverate(23.3%).Investigators
attheUlsanCollegeofMedicineinSouthKoreausedresultsfromtheSOMAscanassayto
constructapanelofsevenproteinbiomarkersthatcoulddiscriminateaKoreancohortwith
non-smallcelllungcancer(NSLC)fromnegativecontrols.Theabilityoftheirproteinpanelto
detecttruepositiveswas75%overalland61.9%forearlystage(stagesI&II)lungcancer.The
seven-markerpaneloutperformedthecommonlungcancermarkerCyfra21-1inidentifying
NSLCatallfourstagesofdisease,withanoverallaccuracyof80.4%comparedto59.5%.The
panelwasalsosuperioratdistinguishingearlystageNSLCfrombenignlungnodules.The
resultsofthisstudycouldbeusefulfordevelopingabetterlungcancerdiagnosticanda
noninvasivetesttoevaluatelungnodulesidentifiedbyCTscreeningfortheKoreanpopulation.
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QiaoZetal.(2017)Proteomicstudyofhepatocellularcarcinomausinganovelmodified
aptamer-basedarray(SOMAscanTM)platform.BiochimBiophysActa1865:434-443.
(Subscriptionrequired).
http://www.sciencedirect.com/science/article/pii/S1570963916301935
Hepatocellularcarcinoma(HCC)isthemostcommonformoflivercanceranditsincidenceis
expectedtocontinuetogrow.AccuratediagnosisandprognosiswouldgreatlyimproveHCC
treatmentsandclinicaloutcomes.Towardsthisend,researchersinJapanusedtheSOMAscan
assaytocompareglobalproteinlevelswithinHCCtumorandnon-tumortissue,aswellas
canceroustissueswithdifferentvascularinvasionstatus.Thelevelsof68proteinsweretumordependent,andeightproteinswereassociatedwithvascularinvasion.Withfurthervalidation
underway,thesedatamayhelpelucidatediseasemechanismsandleadtoimprovedtoolsfor
screeningandevaluatingHCCtherapies.
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Zyba,SJetal.(2017)AmoderateincreaseindietaryzincreducesDNAstrandbreaksin
leukocytesandaltersplasmaproteinswithoutchangingplasmazincconcentrations.AmJ
ClinNutr.105:343-351.
http://ajcn.nutrition.org/content/105/2/343.long
ResearchersattheChildren’sHospitalOaklandResearchInstituteusedtheSOMAscanassayto
analyzeserumfrom18menwhowerefedzinc-fortifiedrice,atypeofdietarysupplement
giventopeopleindevelopingcountries.Theyfoundthatamodestincreaseindietaryzinc
leadstoanincreaseintheconcentrationsofproteinsthatpreventDNAdamage,inflammation
andoxidativestress.Theseresultscouldhelpexplaintheconnectionbetweenzincdeficiencies
andchronicdiseasessuchascancer,diabetesandatherosclerosis.
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RiceLMetal.(2017)Aproteome-derivedlongitudinalpharmacodynamicbiomarkerfor
diffusesystemicsclerosisskin.JInvestDermatol.137:62-70.(Subscriptionrequired).
http://www.jidonline.org/article/S0022-202X(16)32372-7/abstract
Diffusecutaneoussystemicsclerosis(dcSSc)isanautoimmunediseasethatischaracterizedby
excessivecollagendepositionthatcauseshardeningoftheskin.Thediseasecanspreadto
internalorgansincludingtheheart,lungs,andkidneysandcauseorganfailureanddeath.
Testingforserumautoantibodies(i.e.,antibodiesthatattack“self”tissues)canbehelpfulfor
diagnosis,butautoantibodyconcentrationsdonotnecessarilycorrelatewithdcSScseverity,so
theycannotbeusedtomonitordiseaseprogressionortherapeuticresponse.Thegoalofthis
studywastousetheSOMAscanassaytoidentifylongitudinalbiomarkersofdcSSc.Proteomic
analysisofserafromtwoindependentcohortsfound181proteinswithalteredlevelsbetween
dcSScpatientsandhealthycontrols.Eightofthehitsweresubsequentlyvalidated,including
threenewproteinsthathadnotbeenpreviouslyassociatedwithdcSSc.Acombinationoftwo
proteins(ST2andSPON1)robustlydescribedlongitudinalchangesandcouldproveusefulfor
monitoringchangesindcSScpatientsovertime.
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DeGrooteMAetal.(2017)Highlymultiplexedproteomicanalysisofquantiferon
supernatantstoidentifybiomarkersoflatenttuberculosisinfection.JClinMicrobiol.55:
391-402.
http://jcm.asm.org/content/55/2/391.long
Anestimatedtwobillionpeopleareinfectedwithtuberculosis(TB)worldwide,althoughnot
everyonewhoharborstheTBbacteriumwillbecomesick.Eliminatingthediseasewillrequire
bettermethodstoidentifyandtreatthosewithlatentTBinfection(LTBI).Inthispilotstudy,
researchersfromDenverHealthandSomaLogicrantheSOMAscanassayonuntreatedandTB
antigen-stimulatedplasmasamplesfromLTBIpositiveandnegativeindividuals.They
identifiedseveralnewproteinsthatdistinguishedthoseinfectedwithTBfromuninfected
controls.ThesefindingscouldleadtomoreaccuratetestsfordiagnosingLBTIaswellasthe
likelihoodofprogressingtoactiveTB,whichisamajorlimitationofcurrentlyavailabletests.
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HeierCRetal.(2016)Identificationofpathway-specificserumbiomarkersof
responsetoglucocorticoidandinfliximabtreatmentinchildrenwithinflammatorybowel
disease.ClinTransGastroenterol.7:e192.
http://www.nature.com/ctg/journal/v7/n9/pdf/ctg201649a.pdf
Inflammatoryboweldisease(IBD)isachronicconditionwherethebody’simmunesystem
attacksitsowndigestivetract.ThegoalofmostIBDtreatmentsistoachieveremission,
howeverthereisincreasingevidencethatalleviatingthesymptomsdoesnotultimately
improveoutcomes.Repeatedcolonoscopycanbeusedtomonitorpatients’responsetoIBD
therapies,butthetechniqueiscostly,invasiveandcanberisky,particularlyforchildren.In
ordertofindpharmacodynamicbiomarkersofIBD,researchersattheChildren’sNational
HealthCenterinWashington,D.C.rantheSOMAscanassayonpediatricserumsamples
obtainedbeforeandaftertreatmentwithacorticosteroid(prednisone)orabiologic
(infliximab)anti-inflammatorydrug.Theyidentified18proteinsand3miRNAswhoselevels
changedinasimilarmanner(eitherincreasedordecreased)forbothdrugs.Eightofthe
markersthatdecreasedareassociatedwithinflammation,whereasmanythatincreasedare
associatedwithresolvinginflammationandtissuedamage.Withfurthervalidation,these
proteinbiomarkerscouldbeusedtotracktreatment,optimizedosing,andacceleratenew
drugdevelopmentforIBDpatients.
_____
TsimSetal.(2016)DiagnosticandPrognosticBiomarkersintheRationalAssessmentof
Mesothelioma(DIAPHRAGM)study:protocolofaprospective,multicentre,observational
study.BMJOpen6:e013324.
http://bmjopen.bmj.com/content/6/11/e013324.long
Thispublicationdescribestheprotocolforaclinicaltrialtoassesstheperformanceofprotein
biomarkersformalignantpleuralmesothelioma(MPM).MPMisarare,aggressive,pulmonary
cancerthatisusuallycausedbyasbestosexposure.Previously,scientistsatSomaLogicusedthe
SOMAscanassaytodevelopapanelof13proteinsfromserumthatcoulddetectMPMwith
92%accuracy.ThegoalofthisnewstudyistoseewhethertheSOMAscanpanelorfibulin-3(a
potentialplasmabiomarkerofMPM)levelscouldprovideclinicallyusefuldiagnosticand
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prognosticinformation.Anon-invasivetestthatcoulddistinguishMPMfromconfounding
pleuralmalignancieswouldofferamajorclinicaladvanceovercurrentapproaches.
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LynchAMetal.(2016)Therelationshipofnovelplasmaproteinsintheearly
neonatalperiodwithretinopathyofprematurity.IOVS57:5076-5081.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053115/pdf/i1552-5783-57-115076.pdf
Retinopathyofprematurity(ROP)isaneyediseasethataffectssmallerprematureinfantsand
isaleadingcauseofchildhoodblindnessworldwide.NotallprematurebabiesdevelopROP
andnotallbabiesaffectedbyROPexperienceimpairedvisionlaterinlife.However,therisk
factorsfordevelopingclinicallysignificant(high-grade)ROParenotknown.Researchersat
theUniversityofColoradoSchoolofMedicinerantheSOMAscanassayonbloodsamples
obtainedfrompre-terminfantsinthefirstweekoflife,andfoundseveralproteinsthatappear
tobeassociatedwithclinicallysignificantROP.Althoughpreliminary,theseproteinsmaybe
diagnosticofROPseverity,aswellaspotentialtargetsforfuturetherapeutics.Theauthors
notedthattheabilitytomeasurelowabundantproteinswasanimportantadvantageofusing
aptamer-basedtechnologiesforthisstudy.
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BillingAMetal.(2016)ComplementarityofSOMAscantoLC-MS/MSandRNA-seqfor
quantitativeprofilingofhumanembryonicandmesenchymalstemcells.JProteomics
150(6):86-97.
http://www.sciencedirect.com/science/article/pii/S1874391916304006
“Dynamicrange”isperhapsthesinglemostdifficultchallengeinmeasuringtheproteomein
anymeaningfulway.Inotherwords,proteinsarepresentinanygivenbiologicalfluidacrossa
largerangeofconcentrations,greaterthantenlogsofrelativeabundance.Thisparticular
challengeistheonebestaddressedbytheSOMAscanassay,asdemonstratedinthisarticle.A
researchteamatWeillCornellMedicalCollegeinDohar,Qatar(siteofoneofthefirst
installationsoftheSOMAscanassayoutsideofSomaLogic),comparedSOMAscanwithmass
spectrometry(MS)andRNAsequencing(RNA-seq)inanalyzingproteinsfrombothhuman
embryonicandmesenchymalstemcells.InadditiontovalidatingSOMAscanresultswithother,
moretraditionalapproaches,theirresearchunderscoresSOMAscan’s“deepreach”intothe
proteometoidentifythe“rarer”proteinsthatmaybethemostcriticalbiomarkersforarange
ofdiseasesandconditionsofinterest.
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AshleySLetal.(2016)Six-SOMAmerindexrelatingtoimmune,proteaseandangiogenic
functionspredictsprogressioninIPF.PLOSONE11:e0159878.
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0159878
Idiopathicpulmonaryfibrosis(IPF,thethickeningoflungtissue—andthuscompromiseof
breathingleadingtodeath—forreasonsunknown)islikelyseveraldifferentdiseasesatthe
molecularlevel,requiringdifferenttherapeuticapproaches.SomepeoplewithIPFmanage
wellovertime;othersrapidlyprogressanddie.Beingabletotellthedifferenceinanoninvasivemannershouldleadtobettertreatmentdecisionsandoutcomes.Agroupof
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researchersfromMedimmuneandtheUniversityofMichiganappliedtheSOMAscanassayto
bloodsamplesfromagroupofIPFpatientstoidentifypotentialbiomarkersthatdistinguish
long-termnon-progressorsfromthosewhoprogressedquickly.Asix-analyteindex(signature)
ofproteinswasidentified,whichnotonlysuggestsabetterwaytomanagepatientsbutalso
revealssomenovelIPFbiologytofurtherexplore.
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WeltonJLetal.(2016)Proteomicsanalysisofvesiclesisolatedfromplasmaandurineof
prostatecancerpatientsusingamultiplex,aptamer-basedproteinassay.JExtracellVesicles
5:31209.
http://www.journalofextracellularvesicles.net/index.php/jev/article/view/31209
Despitethehighprevalenceofprostatecancer,mostmenwilldiewiththediseaseratherthan
ofit.Thereisahugeunmetmedicalneedtobeabletotellthedifference.Themeasurementof
PSA(prostate-specificantigen)inthebloodisamixedsuccessatbest:Betterbiomarkersare
needed.Inthisstudy,scientistsatCardiffUniversitylookattheproteinprofilesof“exosomes,”
smallvesiclesshedbyvariouscelltypes(includingcancer),todetermineiftheycanpickup
prostatecancer-specificmarkersinthebloodandurineofmetastaticprostatecancerpatients
(andnormalcontrolsforcomparison).Althoughapreliminarystudy,theresearchersestablish
aproofofprincipleforthisapproach,andpreliminarydatathatsuggestitsviability.
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WuDetal.(2016)IncorporationofSOMAmerreagentsinsinglemoleculearrayassaysfor
cytokinedetectionwithultrahighsensitivity.AnalChem.88(17):8385-8389.(Subscription
required).
http://www.ncbi.nlm.nih.gov/pubmed/27529794
Recentconcernsaboutantibodyconsistencyandqualityinbothclinicalandbenchresearch
applicationshavemanyscientistslookingformorereliablealternatives.Inthisarticle,
researchersfromTuftsUniversityandSomaLogicdemonstratethatSOMAmerreagentscanbe
usedinplaceofantibodiesinultrasensitive“singlemoleculearray(Simoa)assays,”
demonstratingtheirefficiencyinmeasuringsixdifferentcytokinetargets.Theauthorssuggest
thatthiscombination“willgreatlybenefitbothbiomarkerdiscoveryanddiseasediagnostic
fields.”
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HathoutYetal.(2016)Serumpharmacodynamicbiomarkersforchroniccorticosteroid
treatmentofchildren.SciRep.6:31727.
http://www.nature.com/articles/srep31727
Corticosteroidsareusedeffectivelyacrossalargenumberofdiseasesandconditionsinwhich
inflammationplaysatleastapartialrole.Butregular,repeatedusecanbringalongahostof
sideeffects,manyofwhichcanbeworsethantheinitialdiseaseorcondition.Inoneparticular
disease,Duchennemusculardystrophy(DMD),corticosteroidsareacurrentstandardofcare,
butefficacygiveswaytosafetyissuesovertime,varyingbypatient.Inthisarticle,a
multicentergroupofresearchersusetheSOMAscanassaytoidentifyproteinbiomarkersof
corticosteroidefficacyandsideeffects,withthegoalofdevelopingadiagnostictoolto
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optimizetheuseofthesepowerfultreatmentsinDMDpatients—andyoungpatientswith
otherdiseases—overtime.
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NgoDetal.(2016)Aptamer-basedproteomicprofilingrevealsnovelcandidatebiomarkers
andpathwaysincardiovasculardisease.Circulation134(4):270-285.(Subscription
required).
http://www.ncbi.nlm.nih.gov/pubmed/27444932
-and-
GramoliniAetal.(2016)Identifyinglow-abundancebiomarkers:Aptamer-based
proteomicspotentiallyenablesmoresensitivedetectionincardiovasculardiseases.
Circulation134:286-289.(Subscriptionrequired).
http://www.ncbi.nlm.nih.gov/pubmed/27444931
FollowingcloselyonthepublicationofresultsfromtheuseofSOMAscantoidentifyevenlowconcentrationproteinchangesthatforetellthepersonalizedriskofcardiovascularevents(see
GanzPetal.,below),thissetofstudiesbyresearchersatBethIsraelDeaconessMedicalCenter
andtheBroadInstituteofMITandHarvarddemonstratesthepoweroftheSOMAscanassay
forfindingnovelbiomarkersofcardiovasculardiseaseinresponsetoa“planned”heartattack
(partofauniquetreatmentprotocolforpatientsundergoingseptalablationforhypertrophic
cardiomyopathy).Notonlywerepotentiallow-abundancebiomarkersconsistentlyrecovered
frompatientsamples,buttheproteinsidentifiedbySOMAscanwerealsovalidatedbyrigorous
massspectrometryanalysis.Therelevanceoftheseto“unplanned”myocardialinfarctionsis
beingfurtherinvestigated.AssummarizedintheaccompanyingeditorialbyAnthony
Gramolini,EdwardLauandPeterLiu,“Ifthesetechnologiescontinuetodevelopapaceas
expected,wecanlookforwardtoabountyofnewinsightsforpatientcareevenfromminute
amountsofliquidbiopsies.”
AccesstoanelectronicversionoftheCirculationpaperandtheaccompanyingeditorial
isavailableonrequest.
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GanzPetal.(2016)Developmentandvalidationofaprotein-basedriskscorefor
cardiovascularoutcomesamongpatientswithstablecoronaryheartdisease.JAMA
315(23):2532-2541.(Subscriptionrequired).
http://www.ncbi.nlm.nih.gov/pubmed/27327800
-and-
SabatineMS(2016)Usingaptamer-basedtechnologytoprobetheplasmaproteomefor
cardiovasculardiseaseprediction.JAMA315(23):2525-2526.(Subscriptionrequired).
http://www.ncbi.nlm.nih.gov/pubmed/27327798
Everypatientdiagnosedwithstablecoronaryheartdiseaseiscurrentlytreatedaggressivelyin
ordertohelppreventanyfuturecardiovascularevents.However,noteverysuchindividualis
atsignificantriskofsuchevents,leadingtoexpensiveovertreatmentandmentalanguish.In
thisbreakthroughstudy,researchersfromUCSFandSomaLogicusedSOMAscantodiscover
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andvalidateagroupofninebloodproteinswhoselevelscanreliablyandaccuratelypredict
whoisathighorlowriskoffutureevents.Theseproteinscanalsobeusedtotrackwhois
gettingclosertoanevent,andwhoisbenefittingfrompreventativeinterventions.The
accompanyingeditorialbyDr.MarcSabatinefromHarvardputsthesefindingsinthecontext
ofemergingpersonalizedorprecisionmedicine,aswellasthepossibilitythatseveralofthe
novelproteinsuncoveredcouldbefuturetherapeutictargets.Adiagnostictestbasedonthese
resultsisunderdevelopmentforreleaselaterthisyear.
AccesstoanelectronicversionoftheJAMApaperandtheaccompanyingeditorialis
availableonrequest.
_____
GuptaVetal.(2016) AnevaluationofanaptamerforuseasanaffinityreagentwithMS:
PCSK9asanexampleprotein.Bioanalysis8(15):1557-1564.(Subscriptionrequired).
http://www.ncbi.nlm.nih.gov/pubmed/27397798
Inthisarticle,aresearchgroupatMerckResearchLaboratoriesfurtherdemonstratesthe
extensiveutilityofindividualSOMAmerreagentsacrossmultiplelifescienceandclinical
applications.TheyuseaparticularSOMAmerreagent,inthiscaseonethatbindsthePCSK9
protein(atargetofgreatinterestincardiovascularmedicine),toenrichtheproteinfrom
patientsamplesforsubsequentanalysisbymassspectrometry.ThePCSK9SOMAmer
performedaswellas—ifnotbetterthan—PCSK9antibodies,butprovidessignificant
advantagesoverthoseantibodiesintermsofconsistency,background,andstability.
LukjanenkoLetal.(2016)Lossoffibronectinfromtheagedstemcellnicheaffectsthe
regenerativecapacityofskeletalmuscleinmice.NatMed.8:897-905.(Subscription
required).
http://www.ncbi.nlm.nih.gov/pubmed/27376579
Musclehasaremarkableabilitytoregenerateitselfviadedicatedmusclestemcellsandtheir
surroundingmicroenvironmentofsignalingandothermolecules(theso-calledstemcell
“niche”).However,thatabilitydecreaseswithage,forreasonsthatarestillunknown.Inthis
paper,aninternationalresearchcollaborationledbyscientistsfromNestleInstituteofHealth
Sciencesundertookaseriesofstudiestodeterminethecause(andpotentialtreatment)of
agingmuscledeterioration.AmongthosestudieswasaSOMAscanassaytodeterminewhat
proteinsmightbealteredintheagedmusclestemcellnichevs.youngermuscle.Theyfound
thatoneproteininparticular,fibronectin,wassignificantlydecreasedintheoldermuscle
tissue,andadditionoffibronectincouldregaintheregenerativecapabilityinthatmuscle.
Theyalsodemonstratethestructuralmechanismbywhichfibronectinhelpsmaintainmuscle
regeneration.Whilefurtherstudiesareneeded,thisisanexcitinginsightintohowtoperhaps
modulateoneofthemoredevastatingbodilyeffectsofaging.
_____
PetekLMetal.(2016)Acrosssectionalstudyoftwoindependentcohortsidentifiesserum
biomarkersforfacioscapulohumeralmusculardystrophy(FSHD).NeuromusculDisord.
26:405-413.
http://www.nmd-journal.com/article/S0960-8966(15)30161-9/pdf
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Facioscapulohumeralmusculardystrophy(FSHD),thethirdmostcommongeneticdiseaseof
skeletalmuscle,isusuallyfirstdiagnosed,progressingtowardsincreaseddisability,decreased
qualityoflife,anddeath.Althoughtherearepotentialtreatments,theslowandoftensporadic
progressionofFSHDmakesitdifficult,atbest,toassesstheirefficacy.Thus,thereisagreat
needforrobust,reliablebiomarkers.Thispreliminarystudy,usingSOMAscan,identified
severalbiomarkersthatappeartocorrelatewithclinicalseverity,thoughfurtherstudiesare
needed.
_____
NishikawaAetal.(2016)Identificationofdefinitiveserumbiomarkersassociatedwith
diseaseactivityinprimarySjögren’ssyndrome.ArthritisResTher.18:106.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868006/pdf/13075_2016_Article_1006.p
df
Sjögren’ssyndrome(SS),anautoimmunediseaseinwhichimmunecellstargetthebody’s
moistureproducingcells,isthethirdmostcommonrheumaticautoimmunedisorder(after
rheumatoidarthritisandsystemiclupuserythematosus).Despiteitsprevalence,SSisnotwell
understood,andtreatmentinterventionshavehadmixedsuccessatbest.Inaneffortto
identifymarkersofdiseaseandpotentialnewdrugtargets,Nishikawaetal.usedSOMAscanin
samplesfrom88patientswithprimarySS(i.e.,patientswithoutotherrheumaticdiseases
noted).Theyidentified82proteinsassociatedwithpSS,nineofwhichwereassociatedwith
diseaseactivityandfiveofthesevalidatedbytraditionalELISA.Largerstudiesareunderway
todetermineadditionalmarkersandtoevaluatethesemarkersaspotentialnewtherapeutic
targets.
_____
MarionTetal.(2016)Respiratorymucosalproteomequantificationinhumaninfluenza
infections.PLOSONE11:e0153674.
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0153674
Influenzavirusseriouslysickensthreetofivemillionpeopleworldwideeachyear,causingan
estimated250,000to500,000deathsannually(WorldHealthOrganization).Thedegreeof
morbidityandmortalitydependsnotonlyonthestrainofvirus,butalsoontheinteractionof
theviruswithhostfactorsofinfectedindividuals.Inoneofthefirststudiesofitskind,an
internationalgroupofresearchersusedSOMAscantounderstandtheintricateinterplayof
hostandvirusproteinsbyidentifyingproteinchangesinnasalsecretionsduringinfectionand
diseaseprogression.Thoughpreliminary,thisstudyprovidesalargenumberofnewinsights
andpotentialnewresearchdirectionsforaddressingthiscommonbutdeadlyvirus.
_____
DroletDWetal.(2016)Fitfortheeye:aptamersinoculardisorders.NucleicAcidTher.
26:127-146.
http://online.liebertpub.com/doi/pdf/10.1089/nat.2015.0573
ThefirstFDA-approvedaptamer-baseddrug,Macugen,wasdevelopedforthetreatmentofthe
“wetform”oftheeyedisorderage-relatedmaculardegeneration(AMD).Twoadditional
aptamer-baseddrugsforAMDareinlate-stageclinicaldevelopment.Thisreviewarticle
coversnotonlythehistoryoftheAMD-directedaptamers,butalsodiscussesthemanyother
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11
potentialtherapeuticopportunitiesforaptamers(includingSOMAmerreagents)in
ophthalmologicalindicationswithsignificantunmetmedicalneed.
_____
MurotaAetal.(2016)Serumproteomicanalysisidentifiesinterleukin16asabiomarkerfor
clinicalresponseduringearlytreatmentofrheumatoidarthritis.Cytokine78:87-93.
(Subscriptionrequired).
http://www.ncbi.nlm.nih.gov/pubmed/26700586
Inthisstudy,researchersfromKeioUniversityandTakedaPharmaceuticalCompanyusedthe
SOMAscanassaytoidentifyblood(serum)-basedbiomarkersofrheumatoidarthritis(RA)that
couldbecorrelatedwithdiseaseprogressionandtreatmentefficacy.ComparingRApatients
withnon-RAvolunteers,theresearchersfoundthattheserumlevelsofinterleukin-16(IL-16)
areabetterindicatorthanothermeasurementincurrentuse,andthusIL-16maybeamore
usefulclinicalbiomarkerofresponsetotreatment.Theyalsonotethatsuchstudieshavebeen
difficulttoimpossibletoperformpriortotheavailabilityofthe“new,reliableand
comprehensive”SOMAscanassay.
_____
SattleckerMetal.(2015)LongitudinalProteinChangesinBloodPlasmaAssociatedwiththe
RateofCognitiveDeclineinAlzheimer'sDisease.JAlzheimersDis.49:1105-1114.
(Subscriptionrequired).
http://www.ncbi.nlm.nih.gov/pubmed/26599049
OneofthemorepowerfulusesoftheSOMAscanassayisinperforming“longitudinal”
proteomics(i.e.,trackingthechangesinproteinlevelsovertime).Inthisstudy,an
internationalgroupofresearcherslookedforchangesinthebloodofpatientswho
transitionedfrommildcognitiveimpairment(MCI)toAlzheimer’sdiseaseoverthecourseof
theyear,comparingthosechangestoindividualswithstableMCI,diagnosedAD,andcontrols
(i.e.,noMCIorAD).Theyfoundthatthelevelsofproteinsknowntobeinvolvedinthe
complementpathwayweresignificantlyelevatedinpatientsundergoingrapidtransitionfrom
MCItoAD.Theseresultsrevealnotonlypotentialnewbiomarkersfortestingtheefficacyof
investigationalADdrugs,butalsosuggestnewdrugtargets.Longer-termvalidationstudies
areunderway.
_____
HirotaMetal.(2016)Chemicallymodifiedinterleukin-6aptamerinhibitsdevelopmentof
collagen-inducedarthritisincynomolgusmonkeys.NucleicAcidTher.26:10-19.
http://online.liebertpub.com/doi/pdf/10.1089/nat.2015.0567
Inthismanuscript,researchersfromSomaLogicandOtsukaPharmaceuticaldescribeaseries
ofstudiesthatdemonstratethattreatmentwithanovelSOMAmerreagentcansignificantly
delaytheonsetandreducetheseverityofrheumatoidarthritis(RA)inacynomolgusmonkey
modelofthedisease.TheSOMAmermoleculeusedinthesestudies,namedSL1026,was
initiallyselectedforitsabilitytodirectlybindandblockthesignalingofthecritical
inflammatoryproteininterleukin-6(IL-6),whichisknowntobeinvolvedinRAonsetand
progression.Becauseitisbasedonnucleicacidsratherthanaminoacids,SL1026offers
certainadvantagesoverantibody-baseddrugssuchastocilizumab,includingthelackofan
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12
immuneresponsetothedrugitself,andamoreconsistentchemicalratherthanbiological
synthesismethod.
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LynchAMetal.(2016)Therelationshipofcirculatingproteinsinearlypregnancywith
pretermbirth.AmJObstetGynecol.214:517.e1-8.(Subscriptionrequired).
http://www.ncbi.nlm.nih.gov/pubmed/26576488
Pretermbirthismajorglobalhealthproblem,andbabiesbornpreterm(<37weekgestation)
haveanelevatedriskofaspectrumofmedicalproblems.Inthispaper,researchersfromthe
UniversityofColoradousedtheSOMAscanassaytoidentifyasignatureofproteinbiomarkers
thatcouldforetellpre-termbirthrisk,withthegoalofmakingsuccessfulearlyintervention
possible.
_____
McArdleAetal.(2016)Developingclinicallyrelevantbiomarkersininflammatoryarthritis:
amulti-platformapproachforserumcandidateproteindiscovery.ProteomicsClinAppl.
10:691-698.(Subscriptionrequired).
http://www.ncbi.nlm.nih.gov/pubmed/26332844
Blood-basedbiomarkersthatcandistinguishbetweenpsoriaticarthritis(PsA)and
rheumatoidarthritis(RA)areasignificantmedicalneed,particularlytoguidetreatment
choiceofavailabledrugs.Inthismanuscript,theauthorscombinethreeproteomics
approachestoidentifysuchmarkers(LC-MS/MS,aLumineximmunoassay,andtheSOMAscan
assay),andcomparetheresults.Theyfound42(LC-MS/MS),3(Luminex),and127(SOMAscan
assay)proteinsrespectivelythatdistinguishbetweenPsAandRApatients.Besidesproviding
thelargestnumberofreproducibleproteinfindings,theSOMAscanassaycovereda
significantlybroaderrangeofthebloodproteomecomparedtotheothertwoapproaches.
_____
OlsonKAetal.(2015)Associationofgrowthdifferentiationfactor11/8,putativeantiageingfactor,withcardiovascularoutcomesandoverallmortalityinhumans:analysisof
theHeartandSoulandHUNT3cohorts.EurHeartJ.6(48):3426-3434.(Subscription
required).
http://www.ncbi.nlm.nih.gov/pubmed/26294790
ThisstudyisparticularlynotableforitsdemonstrationthatGrowthDifferentiationFactor11/8(GDF-11/8)mayplayaroleinhumanssimilartothatseenpreviouslyinmice(see
LoffredoFSetal.2013,below).TheauthorsdemonstratethathigherlevelsofGDF-11/8are
associatedwithalowerriskofcardiovasculareventsanddeathinpatientswithstable
ischemicheartdisease,suggestingthatthemolecularpathwayrepresentedbyGDF-11/8isa
targetforreducingcardiovascularriskassociatedwithaginginhumans.
_____
KiddleSetal.(2015)PlasmaproteinbiomarkersofAlzheimer’sdiseaseendophenotypesin
asymptomaticoldertwins:earlycognitivedeclineandregionalbrainvolumes.Transl
Psychiatry5:e584.
http://www.nature.com/tp/journal/v5/n6/pdf/tp201578a.pdf
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AlthoughtherearenotreatmentsknowntodaythatcandelayorevenpreventAlzheimer’s
disease(AD),havingusefulmarkersofveryearlyonset(pre-symptomatic)iscriticaltotesting
newtherapeuticinterventions.Imagingapproaches(e.g.,MRIorPET)candetectearlysignsof
Alzheimer’s,thoughtheyareexpensiveandrequirehighlevelsofexpertise.Inthisstudyof
asymptomaticoldertwins,theauthorsbuildonearlierworktheyhavedonebyapplyingthe
SOMAscanassaytofindearlybloodmarkersofAD,aswellaslookingatgeneticcontributions.
Theydetectedtwoproteinsinparticular,called“MAPKAPK5”and“MAP2K4,”whichareunder
furtherevaluationnowaspotentialbiomarkersforclinicaltrials.
_____
HattoriKetal.(2015)Increasedcerebrospinalfluidfibrinogeninmajordepressivedisorder.
SciRep.5:11412.
http://www.readcube.com/articles/10.1038%2Fsrep11412
“Majordepressivedisorder”(MDD),likemanycommondiseases,isablankettermforatleast
severaldifferentabnormalitiesatthelevelofproteinand/orgeneticdifferences.Inthis
manuscript,researchersdescribetheuseoftheSOMAscanassaytolookfordifferencesamong
patientsinthelevelsoftheproteinfibrinogenincerebrospinalfluid(CSF),oneofthemany
biologicalfluidsamenabletosuchanalysis.TheydetectedasubsetofMDDpatientswith
increasedfibrinogeninCSF,whichwasverifiedusingtraditionalproteinmeasurementtools.
TheyalsocorrelatedtheincreasedleveloffibrinogenintheCSFwithspecificdamagetothe
brain,particularlyinthewhitematter.
_____
HathoutYetal.(2015)Large–scalebiomarkerdiscoveryinDuchennemusculardystrophy.
ProcNatlAcadSciUSA112:7153-7158.
http://www.pnas.org/content/112/23/7153.full.pdf?with-ds=yes
AlthoughwehaveknownthegeneticcauseofDuchennemusculardystrophysince1986,our
knowledgeoftheactualbiologyofthediseaseanditsprogressionisstillincomplete.Thislack
ofunderstandingseriouslycompromisesoureffortstofindeffectivenewtreatments,aswellas
newdiagnosticteststhatcanhelppatientsandtheircaregiversmanagediseaseprogression.
Thispaper,theresultofafocusedcollaborationbetweenindustry,advocacyandDuchenne
patientadvocates,describesthefirsttrulylarge-scale,unbiasedbiomarkerdiscoveryin
Duchennepatientsvs.controls,usingtheSOMAscanassay.Atotalof44proteinswere
identified,24ofwhichareupand20thataredowninDuchennepatientsascomparedto
controls.Someofthesewereexpected(andconfirmatoryofpreviousstudies),butotherswere
not,andsuggestnewapproachesfordiagnosis,prognosisandnoveltherapeuticdiscoveryfor
thisdevastatingdisease.
_____
MotzerRJetal.(2014)Investigationofnovelcirculatingproteins,germlinesinglenucleotidepolymorphisms,andmoleculartumormarkersaspotentialefficacybiomarkers
offirst-linesunitinibtherapyforadvancedrenalcellcarcinoma.CancerChemother
Pharmacol.74:739-750.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4175044/pdf/280_2014_Article_2539.pdf
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Thedrugsunitinib(SUTENT®)isapprovedworldwidefortreatmentofrenalcellcarcinoma.
However,nogoodbiomarkersforselectinglikelyrespondersandmonitoringtreatment
efficacyhaveyetbeenidentified.Inthisstudy,aresearchteamleadbyPfizerscientists
employedSOMAscan(andseveralothergenomicandproteomicapproaches)todiscoversuch
markersinaphase2clinicaltrialofsunitinib.Twoparticularproteinbiomarkerswere
identifiedthatarenowunderfurtherinvestigationfortheirpredictiveandprognosticvaluein
clinicalsettings.
_____
RohloffJCetal.(2014)Nucleicacidligandswithprotein-likesidechains:modifiedaptamers
andtheiruseasdiagnosticandtherapeuticagents.MolTherNucAcids3:e201.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4217074/pdf/mtna201449a.pdf
AcomprehensivereviewofthedevelopmentofSOMAmerreagentswithanoverviewofthe
manyapplicationsforthesebreakthroughprotein-bindingmolecules.
_____
MenniCetal.(2014)Circulatingproteomicsignaturesofchronologicalage.JGerontolABiol
SciMedSci.70(7):809-816.
http://biomedgerontology.oxfordjournals.org/content/70/7/809.full.pdf+html
AninternationalteamofresearchersusedtheSOMAscanassaytobegintodissectthe
proteomicfeaturesofaginginplasma.Initialfindingfrom202subjectsweresubsequently
replicatedin677additionalsubjects.Theresearchersfoundthat11proteinsofthose
measuredareassociatedwithchronologicalage.Thisinitialstudyunderlinestheimportance
oftheproteomeinunderstandingmolecularmechanismsinvolvedinhumanhealthandaging.
_____
MehanMetal.(2014)Validationofabloodproteinsignaturefornon-smallcelllungcancer.
ClinProteomics11:32.
http://www.clinicalproteomicsjournal.com/content/pdf/1559-0275-11-32.pdf
Buildingonpreviouswork(seeOstroffetal.2010,below),aninternationalgroupof
researchersledbySomaLogicscientistsvalidateaproteinsignatureforthedetectionofnonsmallcelllungcancer.Thispotentialnewtestcouldbeusefulinparticularinfollowuptesting
forpatientsdiagnosedwithalungnoduleusingCTscanning,whichhasonlya4%positive
rateforlungcancerdetection.Theworkisalsonotablefortheapplicationof“Sample
MappingVectors”(i.e.,proteinchangesthatarearesultofbloodhandlingratherthan
biologicalstatus)invalidatingthisproteinsignature.
____
BaumstummlerAetal.(2014)SpecificcaptureanddetectionofStaphylococcusaureuswith
high-affinitymodifiedaptamerstocellsurfacecomponents.LettApplMicrobiol.59:422-431.
http://onlinelibrary.wiley.com/doi/10.1111/lam.12295/epdf
ThisstudybyresearchersfromMerckMilliporeandSomaLogicdemonstratesthebinding
abilityofSOMAmerreagentscreatedagainstbacterialcellsurfaceproteins(inthiscase,S.
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15
aureus),andtheirapplicabilitytothesensitivedetectionofthepathogeninstandard
biodetection,biosurveillanceandfoodsafetyapplications.
_____
MorineMJetal.(2014)Geneticassociationswithmicronutrientlevelsidentifiedinimmune
andgastrointestinalnetworks.GenesNutr.9:408.
http://link.springer.com/article/10.1007%2Fs12263-014-0408-4
Thisproof-of-conceptstudy,publishedbyresearchersatNestléandtheirglobalcollaborators,
describesoneofthefirststudiesthataimstocorrelatemetabolites,geneticvariation,plasma
proteomicchanges,andenvironmentalfactorstobegintounderstandthe“physiological
processesformaintaininghealth.”SOMAscanwasusedforlongitudinalmonitoringofprotein
changesovertwoyearsin45geneticallyuniqueindividualswith61setsofmetabolite,protein
anddietvariables.
_____
MonteiroJPetal.(2014)Methylationpotentialassociatedwithdiet,genotype,proteinand
metabolitelevelsintheDeltaObesityVitaminStudy.GenesNutr.9:403.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4026438/pdf/12263_2014_Article_403.pdf
SimilarinapproachtoMorineetal.(above),thisstudyfromaglobalresearchgroupledby
Nestléscientistsattemptedtomeasureandcorrelatedietaryintakes,micronutrients,and
plasmaproteinstoidentifysubgroupsofindividualsfortargetednutritionalinterventions.
Amongotherresults,itisclearthatmeasuringmultipleproteinstofindpatternsthatcorrelate
withmetabolitelevelsthroughdataminingrevealedtheassociationofcertainmetabolic
pathways(e.g.,hormonalresponses,neuronalresponses,etc.).Proteindifferencesinsex,age,
andweight(obesity)werealsoseen,butfurthervalidationisrequired.
_____
SattleckerMetal.(2014)Alzheimer’sdiseasebiomarkerdiscoveryusingSOMAscan
multiplexedproteintechnology.AlzheimersDement.10:724-734.
http://www.alzheimersanddementia.com/article/S1552-5260(14)00031-4/pdf
BiomarkersthatcanpredicttheonsetofAlzheimer’sdisease(AD)beforetheappearanceof
clinicalsymptoms(i.e.,the“predementiaphase”)arecriticallyneededforthedevelopmentof
earlyinterventiontherapeutics.Inthismanuscript,amultinationalteamofresearchers
describestheapplicationofSOMAscantotheunbiaseddiscoveryofpotentialblood-basedAD
biomarkersassociatedwithvariousaspectsofthedisease.Anumberofproteinbiomarkers
(includingbothpreviouslydescribedandnovelbiomarkers)areshowntobepredictiveofthe
variousaspectsofthedisease,andfurtherevaluationisunderway.
_____
NahidPetal.(2014)Aptamer-basedproteomicsignatureofintensivephasetreatment
responseinpulmonarytuberculosis.Tuberculosis94:187-196.
http://www.ncbi.nlm.nih.gov/pubmed/24629635
Thedesperateneedfornewtherapeuticagentsfortuberculosis(TB)iscompoundedbythe
challengesofevaluatingemergingnewcompoundsearlyandeffectivelyinclinicaltrials.This
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16
manuscriptdescribesaSOMAscan-basedapproachtofindingblood-basedproteinbiomarkers
thatcouldspeedupclinicaldevelopmentofnewtherapeutics,aswellashelpwithmonitoring
patientsonthesenewtreatmentregimes.Theresearchersidentifiedaninitialfiveproteinmarker“signature”thatdifferentiatedbetweentreatmentrespondersandslow-responders,
andwaspredictiveofthecurrentsurrogateendpointusedinTBtherapeutictrials(eightweekculturestatus).
_____
WebberJetal.(2014)Proteomicsanalysisofcancerexosomesusinganovelmodified
aptamer-basedarray(SOMAscan™)platform.MolCellProteomics13:1050-1064.
http://www.mcponline.org/content/13/4/1050.full.pdf+html
Exosomes(smallvesiclessecretedbymost,ifnotall,celltypesintotheblood)couldserveasa
sourceofbiomarkersforearlydetectionofdisease.Inthisstudy,researchersfromCardiff
UniversityandSomaLogicappliedSOMAscantoaprostatecancercellline,hopingtodiscover
betterbiomarkersforearlydetectionofthedisease.Theunbiasedproteinmeasurement
resultedinthediscoveryofover300proteinspreviouslyunassociatedwithprostatecancer,
andestablishesthetechnologyas“aneffectiveproteomicsplatformforexosome-associated
biomarkerdiscoveryindiverseclinicalsettings.”
_____
KiddleSJetal.(2013)CandidatebloodproteomemarkersofAlzheimer'sdiseaseonsetand
progression:asystematicreviewandreplicationstudy.JAlzheimDis.38:515-531.
http://content.iospress.com/download/journal-of-alzheimersdisease/jad130380?id=journal-of-alzheimers-disease%2Fjad130380
Atotalof163candidateblood-basedproteinbiomarkerswerepreviouslydescribedinthe
scientificliteratureforthepotentialdiagnosisofAlzheimer’sdisease(AD).Byapplying
SOMAscan(whichincludesSOMAmersto94ofthe163proteinspreviouslydescribed)toa
largeclinicalsampleset,researchersfromKing’sCollegeLondonandSomaLogicfoundthat9
ofthe94candidatesarereliablyassociatedwithAD-relatedphenotypes,andarenowbeing
validatedasabiomarkersignatureforthedisease(asasetofproteinbiomarkers).
BiomarkersthatcouldpredictonsetandprogressionofADwouldhavegreatutilityclinically,
aswellasforclinicaltrialsandespeciallyintheselectionofsubjectsforpreventativetrials.
_____
OchsnerUetal.(2013)DetectionofClostridiumdifficiletoxinsA,B,andbinarytoxinwith
slowoff-ratemodifiedaptamers.DiagnMicrobiolInfectDis.76:278-285.(Subscription
required).
http://www.ncbi.nlm.nih.gov/pubmed/23680240
Clostridiumdifficile(C.diff)isarapidlygrowinginfectiousdiseasehealththreatworldwide.A
simpleandhighlyspecificdiagnostictestforC.diffwouldhavegreatutilityinboththe
developedanddevelopingworld.Thismanuscriptdescribesthegenerationofspecific
SOMAmerstoseveralC.diff.proteinsand,equallyimportant,thestraightforward
incorporationofSOMAmersintomethodsandplatformsthataremostcommonlyusedfor
antibody-basedtests(i.e.,solutionbinding,pulldownswithbeads,dotblots,andsandwich
assays).
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_____
XieYetal.(2013)InteractionwithbothZNRF3andLGR4isrequiredforthesignaling
activityofR-spondin.EMBORep.14:1120-1126.
http://embor.embopress.org/content/embor/14/12/1120.full.pdf
ProteinsintheWntpathwayareinvolvedintheregulationofmultiplecellularprocesses
(proliferation,cellpolarityandcellfatedetermination),andthusimplicatedinmultiple
cancersandotherproliferativedisorders.Inanefforttofurtherunderstandthepathway,
researchersatNovartisandSomaLogicidentifiedaSOMAmerthatspecificallyneutralizedthe
activityofRSPO1(R-spondin),acriticalmodulatoroftheWntpathway,todetermineitstarget
andsuggestnewtherapeuticapproachestocancerandtissuedegeneration.
_____
LoffredoFSetal.(2013)Growthdifferentiationfactor11isacirculatingfactorthatreverses
age-relatedcardiachypertrophy.Cell153:828-839.
http://ac.els-cdn.com/S009286741300456X/1-s2.0-S009286741300456Xmain.pdf?_tid=f886b958-3165-11e5-909d00000aacb35d&acdnat=1437675153_b2edc94375d8935136162c7cc44d6ecf
Inthismanuscript,ateamofresearchersledbyscientistsfromtheHarvardStemCellInstitute,
describethediscoveryofacirculatingprotein,calledGDF-11(GrowthDifferentiationFactor
11),thatcanreverseage-relatedcardiachypertrophyinmice.Afterfailingtofindthefactor
usinglipidomic,metabolomic,andotherproteomicapproaches,theHarvardteamturnedto
theSOMAscanassay,findingseveralproteins(includingGDF-11)whoselevelsofexpression
changewithage.Theresearchersthendemonstratedthattreatingoldermicewitha
recombinantversionoftheGDF-11proteincanrapidlyreverseage-relatedcardiac
hypertrophy.Studiesaimedatextendingtheseobservationstohumansareunderway.Itis
interestingtonotethat,althoughtheproteinstargetedbySOMAscanarethehumanversion,
sufficientevolutionaryconservationexiststomakeSOMAscanausefultoolforatleastsome
non-humanspeciesapplications.
_____
ParkNJetal.(2013)Measurementofcetuximabandpanitumumab-unboundserumEGFR
extracellulardomainusinganassaybasedonSlowOff-RateModifiedAptamer(SOMAmer)
reagents.PLOSONE8(8):e71703.
http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjourn
al.pone.0071703&representation=PDF
Epidermalgrowthfactorreceptor(EGFR)isacellsurfaceproteinthatisthetargetofthe
anticancerdrugscetuximab(Erbitux®)andpanitumumab(Vectibix®).Inthismanuscript,
scientistsfromQuestDiagnosticsandSomaLogicdescribetheuseofaSOMAmerthatbindsthe
extracellulardomainofEGFRtodeterminetheamountofdrug-unboundEGFRinpatients
beingtreatedwitheitherdrug.Thisassaycouldhelpdeterminedrugefficacyanddosingfor
individualpatients.
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DeGrooteMAetal.(2013).Elucidatingnovelserumbiomarkersassociatedwithpulmonary
tuberculosistreatment.PLOSONE8(4):e61002.
http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjourn
al.pone.0061002&representation=PDF
Thismanuscriptdescribesthefirstlarge-scaleproteomicanalysisemployingSOMAscanina
studyofactivetuberculosis(TB).Theinternationalteamofscientistsidentifiedmultiple
proteinsthatexhibitsignificantexpressiondifferencesduringtheintensivephaseofTB
therapy,inparticulardiscoveringproteinchangesinconservednetworksofbiological
processesandfunction(antimicrobialdefense,tissuehealingandremodeling,acutephase
response,patternrecognition,protease/anti-proteases,complementandcoagulationcascade,
apoptosis,immunityandinflammationpathways).Someofthesewereknownpreviously
(providingvalidationforthework),butmanynovelproteinswerealsoidentified.Thesenewly
identifiedproteinsmayprovidenewinsightsforunderstandingTBdisease,itstreatmentand
subsequenthealingprocessesthatoccurinresponsetoeffectivetherapy.
_____
OstroffRMetal.(2012)Earlydetectionofmalignantpleuralmesotheliomainasbestosexposedindividualswithanoninvasiveproteomics-basedsurveillancetool.PLOSONE
7(10):e46091.
http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjourn
al.pone.0046091&representation=PDF
Thismanuscriptdescribesasetofmulti-centercase-controlstudiesofserumfrom117
malignantmesothelioma(MM)patientsand142asbestos-exposedcontrolindividuals.
Biomarkerdiscovery,verification,andvalidationwereperformedusingtheSOMAscanassay.
From64candidateproteinbiomarkersidentified,theteamofscientistsfromNewYork
UniversityandSomaLogicderiveda13-markerrandomforestclassifierthatdemonstrated
extremelyhighsensitivityandspecificity(97%/92%intrainingand90%/95%inblinded
verification,and90%/89%inasecondblindedvalidationset).Thisresultwasfarsuperiorto
thatofmesothelin,thecurrentlyusedbiomarkerformesotheliomadetection/diagnosis.The
SOMAmerbiomarkerpaneldiscoveredandvalidatedinthesestudiesprovidesasolid
foundationforsurveillanceanddiagnosisofMMinthoseathighestriskforthisdisease.
_____
BairdGetal.(2012)Age-dependentchangesinthecerebrospinalfluidproteomeby
somamerarray.AmerJPathol.180(2):446-456.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3349859/pdf/main.pdf
ThismanuscriptisthefirstpublisheddescriptionoftheuseofSOMAscantoperformunbiased
proteindiscoveryincerebrospinalfluid(CSF),abiologicalmatrixthatmayprovideearly
detectionanddiagnosisforseveralcentralnervoussystem(CNS)degenerativediseases.
ScientistsfromtheUniversityofWashingtonandSomaLogicexaminedtheCSFproteomefrom
90normaladults(ages21–85).InadditiontodemonstratingtheapplicabilityofSOMAscanto
CSF,theydiscoveredasetofproteinchangesthatcorrelatewithincreasingage,afindingthat
mayhaverelevanceindiagnosingage-relatedCNSdiseases.
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19
MehanMRetal.(2012)Proteinsignatureoflungcancertissues.PLOSONE7(4):e35157.
http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjourn
al.pone.0035157&representation=PDF
InthisfirstreportofSOMAscanappliedtotissuesamples,ateamofscientistsfromSomaLogic
andtheUniversityofWashingtoncomparedtheproteinexpressionsignaturesofnon-small
celllungcancer(NSCLC)tissueswithhealthyadjacentanddistanttissuesfromsurgical
resections.Theyfoundthat36proteinsexhibitedthelargestexpressiondifferencesbetween
matchedtumorandnon-tumortissues(20proteinsincreasedand16decreasedintumor
tissue).ThirteenoftheseproteinshavenotbeenpreviouslydescribedinNSCLC.Thesetissue
biomarkersalsooverlapwithacoresetofproteinsidentifiedinalargeserum-basedNSCLC
studywithSOMAscan(seeOstroffRMetal.2010,below).ByusingtheSOMAmerstothe
proteinsidentifiedinthestudyasnovelhistochemicalprobes,thescientistsdemonstratedthat
differencesinproteinexpressionaregreaterintissuesthaninserum(asexpected).The
combinedresultsofthisstudyandtheserumstudypresentthemostextensiveviewtodateof
thecomplexchangesinNSCLCproteinexpressionandhaveimportantimplicationsfor
developmentofnewdiagnosticandtherapeuticapproaches.
_____
GuptaSetal.(2011)Rapidhistochemistryusingslowoff-ratemodifiedaptamerswith
anioniccompetition.ApplImmunohistochemMolMorphol.19(3):273-278.(Subscription
required).
http://www.ncbi.nlm.nih.gov/pubmed/21217521
ThismanuscriptisthefirstdescriptionoftheutilityofindividualSOMAmersas
immunohistochemicalimagingreagents,bothforresearchandpotentiallyclinical(e.g.,
intraoperative)settings.TheuniquespecificityanddissociationkineticsofthetwoSOMAmers
used—againstepidermalgrowthfactorreceptor,EGFR,andhumanepidermalgrowthfactor
receptor2,HER2—allowedthetwocloselyrelatedproteintargetstobedistinguishedin
frozentissuesections.Furtherworkisunderwayforvariousimagingapplicationsof
SOMAmers.
_____
OstroffRMetal.(2010)Unlockingbiomarkerdiscovery:Large-scaleapplicationofaptamer
proteomictechnologyforearlydetectionoflungcancer.PLOSONE5(12):e15003.
http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjourn
al.pone.0015003&representation=PDF
Thismanuscriptdescribesboththefirstlarge-scaleapplicationofSOMAscantoaspecific
diseaseandthemostcompleteclinicalserumproteomeanalysisofnon-smallcelllungcancer
(NSCLC)todate.Archivedserumsamplesfrom1326individuals(including291diagnosed
NSCLCpatientsand1,035heavysmokercontrols)fromfourindependentstudieswere
analyzedwithSOMAscan.A12-proteinbiomarkersignaturewasfoundthatdiscriminated
NSCLCfromcontrolswithhighspecificityandsensitivity(91%/84%intrainingsetsand
89%/83%inaseparateverificationset).Thiswork,whichformsthebasisforanewdiagnostic
testindevelopmentbyQuestDiagnostics,isbeingfurtherextendedandrefined.
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20
II.SOMAscan®/SOMAmer®Technologypublications
GawandeBNetal.(2017)SelectionofDNAaptamerswithtwomodifiedbases.ProcNatl
AcadSciUSA114:2898-2903.
http://www.pnas.org/content/114/11/2898.long
SomaLogicscientistsreportonthegenerationandcharacterizationofSOMAmersthatcontain
twotypesofmodifiednucleotides.ThecurrentSomaLogictechnologyusesbasesthathave
beenmodifiedwithaminoacid-likesidechainsatthe5positionofdeoxyuridine(dU).Now,for
thefirsttime,researchershavecreatedSELEXlibrariesthatalsocontain5-positionmodified
deoxycytosine(dC).EighteendifferentDNAlibrariesweresynthesizedthatcontainedzero,one
orbothmodifiedbases.SELEXwasconductedagainstproproteinconvertasesubtilisin/kexin
type9(PCSK9),ahumantherapeutictargetproteinthathelpsregulatecholesterol.The
aptamerswiththehighestaffinityforPCSK9containedtwomodifications.Similarresultswere
observedwithanothertargetprotein,prostate-specificmembraneantigen(PSMA),a
predictorforprogressionandprognosisofprostatecancer.
TheincreasedchemicaldiversityofSELEXlibrariesshouldexpandtherepertoireofprotein
targets.Inadditiontodisplayingtighterbindingwhilemaintaininghighspecificity,
SOMAmerswithtwomodifiedbasesweresignificantlymoreresistanttodegradationthan
thosewithasinglemodification.Doublymodifiedaptamersalsoshowedgreaterepitope
coverage,whichshouldbeusefulfordevelopingreagentsforassaysthatrequiresimultaneous
bindingtoagivenproteintarget.
_____
CottonRJandGraumannJ(2016)readat:AnRpackageforreadingandworkingwith
SomaLogicADATfiles.BMCBioinformatics17:201.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4857291/
TheSOMAscanassaymeasuresover1,300proteinsinsmallamountsofbiologicalsamples.
ExperimentaldatafromtheSOMAscanassayareprovidedinaproprietary“ADAT”fileformat
thatisdifficulttoimportintonon-SomaLogicsoftwarepackages.Toovercomethislimitation,
tworesearchersatWeillCornellMedicineinQatarhavedeveloped“readat,”afree,open
source,RsoftwarepackagethatallowsuserstoimportandanalyzeSomaLogic’sADATformat
files.
_____
GelinasADetal.(2016)Embracingproteins:structuralthemesinaptamer-protein
complexes. CurrOpinStructBiol.36:122-132.
http://www.sciencedirect.com/science/article/pii/S0959440X16000129
Singlestrandednucleicacidscanfoldintoawidevarietyofdifferentshapes,manyofwhich
canrecognizeandbindothermolecules.Thisreviewsummarizesthedifferentmotifsthathave
beenseeninstructuralstudiesofaptamer-proteincomplexes,includingtheexpanded
structural“vocabulary”madepossiblebymodifyingthenucleicacidbases(e.g.,SOMAmer
reagents).
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21
_____
GoldL(2015)SELEX:Howithappenedandwhereitwillgo.JMolEvol.81:140-143.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661202/
Inthisbriefmini-review,SomaLogicFounderandChairmanLarryGolddescribestheoriginsof
SELEXandaptamers,thelaunchofSomaLogicandSOMAmerreagents,andanticipateswhat
iscomingnext.
_____
CarlsonMetal.(2015)Improvedpreparationof2Mtriethylammoniumbicarbonate.Green
ChemLettRev.8:37-39.
http://www.tandfonline.com/doi/full/10.1080/17518253.2015.1091039
SomaLogicresearchersdescribeanewmethodtogeneratealaboratorychemicalused
extensivelyinmakingSOMAmerreagents,resultinginareductionofcarbondioxidewaste
emissionby~90%overcurrentmethodstogeneratethesamechemical.
_____
WolkSKetal.(2015)Influenceof5-N-carboxamidemodificationsonthethermodynamic
stabilityofoligonucleotides.NucleicAcidsRes.43:9107-9122.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627095/
TheincorporationofDNAbasemodificationsresultsinthehighspecificityforandbroader
rangeofproteintypestargetedbySOMAmerreagents.Inthispaper,theauthorsdelvedeeper
intounderstandingthethermodynamiceffectsofthesemodificationsonthestabilityofthe
SOMAmeroligonucleotides,bothintheirsingle-strandedandduplexforms.Theresultsofthese
studiesdemonstratethat,dependingonthetypeofmodification,theadditioncaneither
destabilizeorfurtherstabilizetheduplexforms,butinthesingle-strandedstate(theusualuse
ofSOMAmerreagentsinbiomarkerdiscoveryorotherassays),themodificationssignificantly
stabilizedtheoligonucleotideshapesascomparedtounmodifiedsingle-strandedDNA.
_____
JarvisTCetal.(2015)Non-helicalDNAtriplexformsauniqueaptamerscaffoldforhigh
affinityrecognitionofnervegrowthfactor.Structure23:1293-1304.
http://www.ncbi.nlm.nih.gov/pubmed/26027732
ThestructuralexplanationforthetightbindingofauniqueSOMAmerreagenttoitstarget
(nervegrowthfactor,orNGF)isdescribedinthispaper,thethirdinaseriesofmanuscripts
definingtheprecisemolecularstructureofspecificSOMAmer:proteinpairs(seeGelinasetal.
2015andDaviesDRetal.2012,below).Liketheprevioustwodescriptions,thestructureofthe
NGFSOMAmerisunlikeanypreviouslydescribed,traditionalaptamerconfigurationand
underlinesthecriticalroleoftheDNAbasemodificationsusedingeneratingSOMAmer
reagents.
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22
RohloffJCetal.(2015)Practicalsynthesisofcytidine-5-carboxamide-modifiednucleotide
reagents.NucleosidesNucleotidesNucleicAcids34:180-198.
http://www.tandfonline.com/doi/pdf/10.1080/15257770.2014.978011
TheexquisitespecificityofSOMAmerreagentsfortheircognateproteinsliesintheirexpanded
chemicaldiversityovertraditionalaptamersviatheprotein-likemodificationsaddedtothe
chemicalstructureofsomeofthenucleotidesthatmakeuptheSOMAmersequence.This
manuscriptdescribesthefurtherexpansionofthatchemicaldiversitythroughthesuccessful
effortsofSomaLogicscientiststoaddchemicalmodificationstocytidine(C).These
modificationsdonotinterferewitheithersolid-statesynthesisorenzymaticsynthesisof
oligonucleotidescontainingsuchmodifiedCbases.ModifiedCbasesarealreadybeing
incorporatedintonewSOMAmerdiscoveryexperiments.
_____
OchsnerUAetal.(2014)Systematicselectionofmodifiedaptamerpairsfordiagnostic
sandwichassay.BioTechniques56:125-133.
http://www.biotechniques.com/multimedia/archive/00231/BTN_A_000114134_O_23185
5a.pdf
Thismanuscriptisthefirstpublisheddescription(proof-of-concept)oftheuseofSOMAmersin
asandwichassay.Inthispaper,SOMAmerpairsweregeneratedagainstbothClostridium
difficilebinarytoxinandforagroupofsevenproteinspreviouslyshowntobepromising
biomarkersforcardiovascularrisk.TheabilitytouseSOMAmerpairsindiagnostic
applicationsratherthantraditionalantibodypairsholdspromiseforaccelerateddevelopment
ofrapidtestsand/orspecificdiagnosticpanels.
GelinasADetal.(2014)Crystalstructureofinterleukin-6incomplexwithamodified
nucleicacidligand.JBiolChem.289:8720-8734.
http://www.jbc.org/content/289/12/8720
–and–
GuptaSetal.(2014)Chemically-modifiedDNAaptamersbindinterleukin-6withhigh
affinityandinhibitsignalingbyblockingitsinteractionwithinterleukin-6receptor.JBiol
Chem.289:8706-8719.
http://www.jbc.org/content/289/12/8706
Thispairofpapers,publishedsimultaneouslyintheJournalofBiologicalChemistry,describe
thedevelopmentofnewSOMAmerreagentsthatcanblocksignalingbyinterleukin-6(IL-6,a
criticalproteininvolvedininflammationandcancer),aswellasthestructuralinteractionof
theIL-6SOMAmeranditstargetprotein.Thisworkbothconfirmstheuniqueprotein-binding
propertiesofSOMAmersandunderlinestheirpotentialasanewclassoftherapeuticreagents.
TheworkwasdoneincollaborationwithOtsukaPharmaceuticalsandEmeraldBio.
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23
BrodyEetal.(2012)Life’ssimplemeasures:unlockingtheproteome.JMolBiol.422:595606.(Subscriptionrequired).
http://www.ncbi.nlm.nih.gov/pubmed/22721953
ThisreviewarticledescribesboththeSOMAmer/SOMAscantechnologyandgivesexamplesof
itsmultipleapplicationsinunbiasedproteinbiomarkerdiscovery.Italsoincludesadescription
ofthebioinformaticsmethodsusedtointerpretthelargedatasetsgeneratedbySOMAscan.
_____
DaviesDRetal.(2012)Uniquemotifsandhydrophobicinteractionsshapethebindingof
modifiedDNAligandstoproteintargets.ProcNatlAcadSciUSA109:19971-19976.
http://www.pnas.org/content/109/49/19971.full.pdf+html
ThismanuscriptisthefirstdemonstrationoftheuniquemolecularstructureofaSOMAmer
reagentboundtoitsspecificproteintarget.Theanalysesrevealthemolecularbasisforthe
vastimprovementinproteinbindingbySOMAmersascomparedtotraditionalaptamers,
emphasizingthatSOMAmersrepresentanentirelynewclassofmolecular“affinityreagents”
withmultipleusefulapplicationsinlifesciencesandmedicine.Thisworkwasdoneasa
collaborationbetweenSomaLogicandEmeraldBio.
_____
GoldLetal.(2012)AptamersandtheRNAworld,pastandpresent.ColdSpringHarb
PerspectBiol.4:a003582.
http://cshperspectives.cshlp.org/content/4/3/a003582.full.pdf+html
ThisreviewarticleclearlylaysoutthereasoningandthedevelopmentofSOMAmersthat
wouldprovidetwosimultaneouselementsofspecificity(e.g.,theequivalenttoagoodantibody
sandwichassaywithinasingleSOMAmerreagent).Thosetwoelementsare(1)affinityfor
theirtargetprotein(i.e.,pMorlowerKd),and(2)akineticcomponent(slowoff-rate,or
remarkableslowdissociationrateconstants).Thesetwoproperties,alongwiththechemical
basisforSOMAmers,overcomethespecifictechnicalchallengesfacedbyothercurrent
proteomictechnologies,andprovidethebasisforthestepscomprisingtheSOMAscanassay.
_____
KraemerSetal.(2011).FromSOMAmer-basedbiomarkerdiscoverytodiagnosticand
clinicalapplications:aSOMAmer-based,streamlinedmultiplexproteomicassay.PLOSONE
6(10):e26332.
http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjourn
al.pone.0026332&representation=PDF
ThismanuscriptdemonstratesthattheSOMAscanassayprovidesaseamlesstransitionfrom
SOMAmer-basedbiomarkerdiscoverytoroutineproteinmeasurementsfordiagnosticand
researchpurposes.Furthermore,theassaycanbesemi-automated(heretheydevelopeda
plate-basedversion),andcanbeperformedwithmultiple“backend”readouts(qPCR,beadbased—e.g.,Luminex,etc.),underliningthecompatibilityofthisapproachwithcurrent
nucleic-acidbaseddiagnostictechnologies.
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24
BrodyEetal.(2010)High-contentaffinity-basedproteomics:unlockingproteinbiomarker
discovery.ExpRevMolDiagn.10:1013-1022.
http://www.tandfonline.com/doi/full/10.1586/erm.10.89
ThisreviewarticlecomparestheSOMAscanassaydirectlytoothercurrentproteomic
technologies(massspectrometryandantibody-based),particularlyinhigh-contentprotein
biomarkerdiscovery.ItdemonstrateshowSOMAscanovercomesthespecifictechnical
challengesfacedbytheseotherapproaches,particularlytheneedforhighcontentwithhigh
sensitivityandspecificitytoaddressthecirculatingproteome.
_____
VaughtJDetal.(2010)ExpandingthechemistryofDNAforinvitroselection.JAmChemSoc.
132:4141-4151.(Subscriptionrequired).
http://www.ncbi.nlm.nih.gov/pubmed/20201573
Thismanuscriptdescribesthefundamentalbiochemicalstepsnecessarytoincorporate
modifiednucleotidesintoDNA-basedaptamers(andthusthefirstpublisheddescriptionof
“SOMAmers,”thoughthenamewassubsequentlycoined).Themanuscriptalsodescribesthe
identificationofamodifiedDNAaptamerwithhighaffinityforthetumornecrosisfactor
receptorsuperfamilymember9(TNFRSF9),aproteinthathadprovenrefractorytoaptamer
selectionusingtraditionalunmodifiedDNAaptamers.
_____
GoldLetal.(2010)Aptamer-basedmultiplexedproteomictechnologyforbiomarker
discovery.PLOSONE5(12):e15004.
http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjourn
al.pone.0015004&representation=PDF
ThismanuscriptisthefirstpublisheddetaileddescriptionofthebreakthroughSOMAmerbasedSOMAscantechnology,anddemonstratesitspowerthroughapplicationtosamplesfrom
patientswithchronickidneydisease,findingnotonlyknownmarkersofthediseasebutmany
previouslyunknownproteinbiomarkers.
(Companionpaper,OstroffRMetal.(2010)—abovein“SOMAmer/SOMAscanApplications”).
_____
ZichiDetal.(2008)Proteomicsanddiagnostics:Let’sgetspecific,again.CurrOpinChem
Biol.12:78–85.(Subscriptionrequired).
http://www.ncbi.nlm.nih.gov/pubmed/18275862
Thismanuscriptdescribestheinherentspecificitylimitationsofantibody-basedarraysfor
large-scalebiomarkerdiscovery,andintroducesthebasicideabehindtheSOMAmerreagent
anditstwoelementsofspecificity(i.e.,highaffinityandslowdissociationrates).
_____
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25
EatonBEetal.(1995)Let'sgetspecific:therelationshipbetweenspecificityandaffinity.
ChemBiol.2(10):633-638.
http://ac.els-cdn.com/1074552195900233/1-s2.01074552195900233main.pdf?_tid=2d0444ae-3169-11e5855b00000aacb35d&acdnat=1437676530_f6803454a6da15b1b8b669dc920c5086
Thisreviewarticlelaysoutasystematicargumentforselectingmoleculesthatbindwithhigh
specificitytoaparticulartargetbyscreeningformoleculeswithhighaffinitytothattarget.It
appliesthatunderstandingtotheselectionoftraditionalaptamers,suggestingthecriticalrole
aptamer-basedreagentscanplayindiagnosticandtherapeuticapplications.
_____
JenisonRDetal.(1994)High-resolutionmoleculardiscriminationbyRNA.Science
263:1425-1429.(Subscriptionrequired).
http://www.ncbi.nlm.nih.gov/pubmed/7510417
--and--
ZimmermanGetal.(1997)Interlockingstructuralmotifsmediatemoleculardiscrimination
byatheophylline-bindingRNA.NatStructBiol.4:644-649.(Subscriptionrequired).
http://www.ncbi.nlm.nih.gov/pubmed/9253414
Thesetwomanuscriptstogetherdescribe(1)theisolationofanRNA-basedaptamerthatcan
bindtheophyllinewitha10,000-foldbetteraffinitythanitbindsthecloselyrelatedcaffeine
molecule(whichdiffersfromtheophyllinebyonlyanextramethylgroup)and(2)the
structuralbasisofthataffinity.Theseearlystudiesoftheincrediblespecificitythatcanbe
achievedwithtraditionalaptamersarebeingevenmorefullyrealizedwiththeworkbeing
donewithSOMAmerreagentstoday.
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26