Download pdf - CRT LICENSING OPPORTUNITIES - Cancer Research

CRT has over 200 oncology-focused projects under development and potentially available for licensing or collaboration. All are involved in the fight against cancer and include novel chemotherapeutic and biological agents, diagnostic methodologies and enabling technologies. The projects range from new targets to therapies in pre-clinical development to those in Phase I/II clinical studies.

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CRT LICENSING OPPORTUNITIES

CRT LICENSING OPPORTUNITIES Updated March 2017

SMALL MOLECULES

• Chk2InhibitorProgramme• FirstinClassIKKAlphaSelective

Inhibitors• Novel dual inhibitors of FLT3 and

Aurora Kinases

BIOLOGICAL THERAPEUTICS

• CEA Antibodies• αvß6-binding Peptides for Tumour

Targeting• MUC1 Antibodies• IGF2-TrapTherapy• αvß6 Antagonistic Antibodies• TACE Antibody• Jagged1 Monoclonal Antibody• Anti-CD55 Antibodies• LMP2-TCellReceptor• S100A4NeutralisingAntibody• CCR4• p53TCRMimic• CLEC14a

DIAGNOSTICS

• αvß6 Binding Peptides for Imaging• MCMLung

ENABLING TECHNOLOGY

• Optimam Mammography ImageDatabase&ViewingSoftware

• Imaging Agent for Prostate andGlioma Tumour Detection

• RALA

MEDICAL DEVICES

• BiologicalFluidFiltrationDevice

NEW AND OTHER OPPORTUNITIES

• IBISSoftware(Tyrer-CuzickModel)• S100A4NeutralisingAntibodyfor

Inflammatory Diseases

Chk2 Inhibitor Programme

Lead Optimisation ApotentandselectivecompoundserieswithlownMactivityagainsttheChk2cell-cyclecheckpointkinasehasbeendeveloped.Chk2isacancertargetinvolvedincellcyclearrestandhomologousrecombinationDNArepair.Thisprogramme currently comprises novel patented compounds, established biological assays and co-crystallographic methods to support and inform ongoing medicinal chemistry. The compound series demonstrates inhibition of Chk2incellularassaysandinvivoxenografts,aswellasgoodADMETandphysicochemicalproperties.CRTisnowseekingacommercialpartnerinterestedinpursuingaco-developmentordirectlicensingarrangement.

Contact: Angus Lauder, [email protected]

First in Class IKK Alpha Selective Inhibitors

Lead Optimisation InhibitionofNF-KBsignallingisanattractiveapproachininflammationandcancerandtheIkappaBkinases(IKK’s)aretractabletargetswithinthispathway.However,emergingevidencesuggeststhatinhibitionofIKKßmayhaveclinicalsideeffectsandassuchselectiveIKKαinhibitorsmaybeattractivecandidates.IKKα hasbeenlinkedtoanumber of cancers and our unpublished data has identified a stratified population of prostate cancer patients where inhibitionofIKKαcouldbeapplied.OurprogrammehasalsoidentifiedthefirstreportedpotentandselectiveIKKα inhibitorsandthecompoundsarewellplacedtodeliveraclinicalcandidate.CRTisseekingaco-developmentorlicensing partner to drive candidate selection and entry into formal pre-clinical studies.


Novel dual inhibitors of FLT3 and Aurora Kinases

Clinic Ready Potent, orally bioavailable dual inhibitors of FLT3 (including clinically relevant FLT3-ITD-TKD mutant forms) and Aurora kinases have been developed. The strategy of dual FLT3/Aurora inhibition in a single agent has the potential to overcome the need for combination therapies in AML, and is predicted to have improved efficacy in FLT3-ITD+ AML and reduced susceptibility to resistance. Dual FLT3/Aurora kinase inhibitors also have potential for the treatment of other cancers. The Clinical Development Candidate demonstrates single agent growth inhibition in FLT3-ITD+ human AML xenografts in vivo, and overcomes mutation-driven resistance to selective FLT3 inhibition in AML xenograft in vivo. The project is ready to progress to the clinic, with pre-clinical toxicology studies completed, bulk API manufactured and a clinical protocol prepared. CRT is seeking a co-development or licensing partner to take the Clinical Development Candidate into Phase I clinical studies.

Contact: Tanya Moore, [email protected]

SMALL MOLECULES


CEA Antibodies

Pre Clinical MFE-23isasinglechainFvantibodythathashighaffinityforthetumourspecificantigenCEA.Successfulpreclinicaland clinical studies support its potential for use in a number of applications. These include Phase I studies conducted withradiolabelledMFE-23foruseasanimagingagent,forradioimmunoguidedsurgery,andasthetumour-targetingmoietyofanantibodydirectedenzymeprodrugtherapy.HumanisedMFE-23andhigheraffinityvariantsarealsoavailable.CRTisseekingtosecureacommercialpartner(s)todeveloptheseantibodiesfortherapeutic,imagingand/ordiagnosticpurposes.Collaborationsand/orfield-exclusiveandnon-exclusivelicencesareavailable.

Contact: Jesse Toe, [email protected]

αvß6-binding Peptides for Tumour Targeting

In Vivo Proof-of-Principle Peptides which selectively bind to the integrin αvß6withhighaffinityhavebeendeveloped.Thestructuralmotifrequired for binding has been elucidated, and the consensus sequence is protected by a patent application. The peptidestargettumours(includingoral,pancreatic,ovarian,lung,colorectalandbreast)andfibroticlesionsinwhichtheintegrinisover-expressed.Thepeptideshaveutilityasimagingagentsaswellasforcancertherapyviatargetingof payloads and functional inhibition of αvß6. αvß6playsmultipleregulatoryfunctionsintumoursincludingTGFßactivation, cell proliferation, MMP production, cell invasion and survival. The ability of radiolabelled versions of the peptide to selectively localise to αvß6-expressingxenograftsin vivo, including breast and pancreatic, has been demonstratedbyPETandSPECT.CRTisseekingtosecureacommercialpartner(s)todevelopthesepeptidesfortherapeutic,imagingand/ordiagnosticpurposes.Collaborationsand/orfield-exclusiveandnon-exclusivelicencesare available.


MUC1 Antibodies

In Vivo Proof-of-Principle MUC1,atransmembranemucinfamilyprotein,ishighlyexpressedinanunderglycosylatedforminmultipletumourtypesofepithelialorigin,includingover90%ofbreastcancers.Theglycosylationchangesexposenewpeptideepitopesandoligosaccharides,makingMUC1anattractivetargetforantibodyapproachesthatexploitthetumourspecificepitopescreated.SeveralantibodieswereraisedagainstMUC1andarecommercialisedbyCRT.Weareseekinglicenseesforapackageofpatents,materialsandknow-howfordevelopmentoftheseantibodies.

Contact: Irene Patzak, [email protected]

IGF2-Trap Therapy

In Vivo Proof-of-Principle AnovelIGFpathwaytherapeuticfortreatmentofarangeoftumoursthatareassociatedwithgainoffunctionofIGF2includinghepatocellularcarcinoma,sarcomas,adrenocorticalcarcinomas,breast,lung,prostateandcolorectalcancers.Theleadhighaffinity(sub1nMKd)Insulin-likeGrowthFactor2specificLigandTrap(IGF2-Trap)comeswithanextensivedatapackageincludingproteinsequenceoptimisation,Fcfusionconstructs,invitroassays,anddemonstrationofanti-IGF2activityin vivo(hypoglycaemicmodel)recentlypublishedinPNASPMID:27140600. CRTisseekingapartnertotakethetherapeuticforwardintoclinicaldevelopment.

Contact: Chris Baker, [email protected]



αvß6 Antagonistic Antibodies

Lead Optimisation αvß6 integrin is a promising target for cancer therapy. It plays an active role in tumour progression and its high expressionislinkedtopoorprognosisinmanytumourtypes.HumanisedsinglechainFvandfullIgGantibodieshave been developed by inserting a proprietary short αvß6 binding peptide into a proprietary scaffold. The antibodies showremarkablebindingselectivityforαvß6. In vitrostudiessupporttheirpotentialutilitytoblockαvß6-mediated cancercellinvasionortodeliverandinternalisetoxinsspecificallytoαvß6-expressingtumours.CRTisseekingacollaborative or licensing partner for the further development of anti-αvß6 antibodies.


TACE Antibody

Pre Clinical Candidate TACE(ADAM17)isamembranemetalloproteasethatcleavesandreleasesanumberofsubstratesincludingEGFfamilygrowthfactors,receptorssuchastheIL6receptorandnaturalkillercellregulatorslikeMICA.ManyofthesesubstrateshavebeenlinkedtothegrowthandtherapeuticresponseoftumoursandtheirlevelsarecontrolledbyTACEmakingthisaninterestingtarget.Apackageofdataexistsshowingin-vivomodulationofTACEsubstratesandinitial in vivoactivityusingourleadhumanantibodyD1(A12)anantagonisticantibodythatpotentlyinhibitsTACEactivity.D1(A12)isselectiveforTACEandbindsthehumanTACEprotein(butnotmurineversion).CRTisseekingacommercialpartnertotaketheleadantibodyintoformalpre-clinicalstudiesandapackageofdataandUS/EUpatents are available for licensing.


Jagged1 Monoclonal Antibody

In Vivo Proof-of-Principle Theleadanti-Jagged1monoclonalantibodies(mAbs)comewithastrongdatapackagedemonstratinghighspecificityandlownMaffinitybinding,aswellashavingbeenhumanisedanddeimmunisedbyLonza.Thereisclearin vitroinhibitoryactionagainstJagged1anditsdownstreamtargets.Efficacyhasbeendemonstratedin vitroin3Dspheroids to a similar degree as the pan-Notch γ-secretase inhibitors and in vivo in breast cancer and ovarian cancer xenograftmodels.TheybindtoanovelJagged1epitopethatdistinguishesthemfromothersinthefieldasoutlinedfurtherinourpatentapplicationWO2014111704.CRTisseekingaco-developmentpartneroralicenseetotakethemAbs forward into clinical development.


Anti-CD55 Antibodies

Discovery CD55isacomplementregulatoryproteinoverexpressedonanumberoftumoursandprotectsthetumourcellsfromcomplement-dependentcytotoxicity(CDC).Achimericantibodyhasbeendevelopedfromamouseanti-CD55antibodythathasbeenextensivelyusedintheclinicasanimagingagentwithnoobservedantibody-associatedtoxicity.BlockingCD55usingCRT’schimericanti-CD55antibodyhasthepotentialtoelicitbothCDCandantibody-dependentcell-mediatedcytotoxicity(ADCC)offeringnewtherapeuticavenuesbothaloneandincombinationwith other agents. The project comes with granted patents with the potential to generate novel IP through further development. Both the chimeric and mouse antibodies are available for licensing and/or collaboration.

Contact: Fiona Middleton, [email protected]



LMP2-T Cell Receptor

Pre Clinical ResearchersfromtheUniversityofBirminghamhavedevelopedanovelT-cellreceptor(TCR)targetingtheviralproteinLMP2inEpsteinBarrVirus(EBV)-associatednasopharyngealcarcinoma(NPC).EBVisdetectedinalmostallNPCpatientsandisstronglyassociatedwithNPCpathogenesisthroughHLA-restrictedalleles.NPCisunusuallycommoninSoutheastAsiaandChina,whereitaccountsfor63%ofthe87,000casesofNPCworldwide.Consequently,anHLAA*1101restrictedTCRwasselectedfordevelopmentsincethisalleleisfoundinasignificantproportionofpeopleofChineseandSoutheastAsianorigin.ThegenetransferapproachoftheLMP2-TCRenablessignificantlyfaster(48h)preparationofpatient-derivedT-cellscomparedtothe9weeksforalternativeco-culturemethodsforautologouscelltherapies.Wehavedemonstratedexcellentin vivoefficacywithnoobservedtoxicities.ThistechnologyisalsosuitableforotherEBVcancersexpressingLMP2including,NK/T-celllymphomaandaround10%ofgastriccancers.ApatentcoveringthetechnologyandtherelevantsequencesisinPCTphase.CRTisseekingapartnerexperiencedinthefieldofcelltherapydevelopmentandintheChineseregulatoryenvironmenttotakethistechnology through to first in man trials in China via a licence or collaborative route.

Contact: Tommy Rennison, [email protected]

S100A4 Neutralising Antibody

In Vivo Proof-of-Principle S100A4isacalciumbindingproteinwhichinteractswithandregulatesmultiplecancer-relevantcellsignallingpathways,suchasapoptosis,proliferation,motility,invasionandangiogenesis.S100A4hasawell-validatedrolein metastasis and tumour progression and has been associated with poor prognosis in a number of solid tumours. Amousemonoclonalanti-S100A4antibodyhasbeendevelopedthathashighaffinityandspecificityforthemetastasis-associatedprotein,ishighlyselectiveagainstotherS100proteinsandcomeswithastrongpackageofin vivo proof of concept data as an anti-metastatic therapy. In addition, data suggest the antibody may have an immunomodulatoryeffectbyreversingtheTh2:Th1phenotypeinT-cellsanddelaysprimarytumourgrowth.Apatenthasbeenfiledtoprotecttheleadantibodyandnovelepitope.CRTisseekingapartnerforcollaborationorlicensing to further develop this antibody.


CCR4

In Vivo Proof-of-Principle FullyhumanIgG1anti-CCR4antibodiesareavailableforlicensingand/orcollaborativedevelopment.Duetoitsexpressionontumourinfiltratingimmunecells,includingregulatoryT-cellsandpro-tumourM2macrophages,chemokinereceptorCCR4representsanexcitingtargetforcancerimmunotherapy.AlthoughCCR4isknowntobehighlyexpressedinhaematologicalcancersofT-cellorigin,recentdatafromProfessorFranBalkwill(QueenMaryUniversityofLondon)alsosuggestatherapeuticpotentialforanti-CCR4antibodiesinsolidcancerindications,includingrenalcellcarcinoma(RCC).In vivo efficacyofourantibodieshasbeendemonstratedinbothanadult TcelllymphomaxenograftmodelandanorthotopicsyngeneicmodelofRCC.MechanismofactionstudiescarriedoutincollaborationwithProfessorBalkwilldemonstratethattheantibodiesfunction(atleastinpart)byrepolarisingthetumourmicroenvironment,throughpromotinganincreaseinTh1typeversusTh2typecytokinesandinducinga pro-tumour M2 to anti-tumour M1 macrophage switch, suggesting that treatment with our antibodies would be advantageousinhighlyimmunosuppressivemicroenvironments.Thedual‘function-blocking’and‘ADCC’propertiesof the antibodies suggest an advantage over competitor programmes.

Contact: Lara Boyd, [email protected]



p53 TCR Mimic

In Vivo Proof-of-Principle ThisopportunityhasproducedaleadT-CellReceptormimic(TCRm)monoclonalantibody(mAb)againstanHLA-A*0201presentedpeptidederivedfromthecancertargetp53,thatismutatedin50%ofhumantumoursand deregulated in many more. Currently we have selectivity and specificity data on the lead mAb, with positive preliminarydataforAntibodyDependentCell-mediatedCytotoxicity(ADCC),ComplementDependentCytotoxicity(CDC),AntibodyDependentCellularPhagocytosis(ADCP),aswellasin vivoefficacydatainamousexenograftmodel.InadditiontheantibodyisshowntointernalisemakingitsuitableforuseinanAntibodyDrugConjugate(ADC)approach.CRTisseekingaco-development/licensingpartnertotaketheantibodyforwardintoclinicaldevelopment, and would be happy to provide more data under CDA as our PCT patent application is currently unpublished.


CLEC14a

In Vivo Proof-of-Principle CLEC14A is a novel target of high interest for anti-angiogenesis therapies. This is mainly due to its specific expression in tumour endothelial cells. CRT has generated murine monoclonal antibodies recognising both human and mouse CLEC14A and is currently evaluating them in vivo as naked Abs and ADCs. Both approaches have demonstrated the ability of CLEC14A inhibition to substantially reduce the tumour burden as well as inhibit cell migration and invasion. CRT is seeking to exclusively license the patent application and related know how / materials for development of anti-CLEC14A antibody based therapy.

Contact: Tassos Konstantinou, [email protected]



αvß6 Binding Peptides for Imaging

In Vivo Proof-of-Principle Peptides which selectively bind to the integrin αvß6withhighaffinityhavebeendeveloped.Thestructuralmotifrequired for binding has been elucidated, and the consensus sequence is protected by a patent application. The peptideshaveutilityfortargetingtumours(includingoral,pancreatic,ovarian,lung,colorectalandbreast)andfibroticlesionsinwhichtheintegrinisover-expressed.Thepeptideshaveapplicationsintumourimagingaswellasincancer therapy via targeting of payloads and functional inhibition of αvß6. αvß6 plays multiple regulatory functions intumoursincludingTGFßactivation,cellproliferation,MMPproduction,cellinvasionandsurvival.Theabilityofradiolabelled versions of the peptide to selectively localise to αvß6-expressingxenograftsinvivo,includingbreastandpancreatic,hasbeendemonstratedbyPETandSPECT.Collaborationsand/orfield-exclusiveandnon-exclusivelicences are available.


MCM Lung

Diagnostic Over1.3millionpeopleworldwidearediagnosedwithlungcancereachyear.CRT’stechnologyoffersarapidandcosteffectiveapproachforthediagnosisoflungcancerbasedonMCMdetectioninsputum.Astudyof597patients has revealed that combining sputum MCM immunocytochemistry testing with chest X-rays offers equivalent sensitivity and specificity values as the standard diagnostic approach of sputum cytology and X-rays. The MCM/X-rays combination test provides the advantage of being a simpler and more rapid procedure. In addition, the method has the potential to significantly decrease the number of patients requiring follow-on diagnostic testing andremovestherequirementforahighlyskilledcytopathologistatinitialdiagnosis,resultinginasubstantialcostsaving.CRTislookingforapartnertodevelopaMCMsputum-baseddiagnostictestunderalicencetoagranted multiple-territory portfolio of patents on the target antigen and MCM specific antibodies.

Contact: Julie Little, [email protected]

DIAGNOSTICS


Optimam Mammography Image Database and Viewing Software

Software The database has been created to support research involving medical imaging aimed at optimising the use of existingandadoptionofnewX-rayimagingtechnologies,includingdigitalbreasttomosynthesis(DBT),fordetectingbreastcancersandimprovingearlydetectionintheNHSScreeningProgramme.Thisveryvaluabledatabaseisconstantlybeingaddedtoandcurrentlycontainsover80,000processedandunprocesseddigitalimages,typically for women who have had screen detected breast cancer. The images are annotated with the location andappearanceofcancers,andwhereapplicable,expertdeterminedgroundtruthsdescribingfeaturesofinterestareadded.MedXViewerisaseparatebespokesoftwareapplicationdesignedtoallowworkstationindependent,PACS-lessviewingandinteractionwithmammographyimages.Regionsofinterestcanbeidentifiedbyauserandanyassociatedinformationaboutamark,animageorastudycanbeadded.Theflexiblesoftwaredesignallowstheapplicationtobeeasilyextendedtosupportotherimagingmodalities.Imagesandsoftwareareavailableforlicensing.CRTisalsoseekingcollaborativepartnersinterestedinusingandhelpingtodeveloptheavailabletools.

Contact: Julie Little, [email protected]

Imaging Agent for Prostate and Glioma Tumour Detection

In Vivo Proof-of-Principle Ourtracer18F-FDMPisbasedonapivalicacidstructureandisdesignedforimagingthefirststepsoflipidmetabolism.Wehavetestedthistracerintheindicationsofbreast,prostateandbraintumours,whereitperformedbetterthanthegoldstandard18F-FDG.Weanticipateutilityinagreaterrangeofindications,includinginflammatorydisordersandbrainlesions.Duetoitscomposition,theimagingagentcanbelabelledtobeusedinPET,SPECTandDNPimaging.CRTisseekinglicenseesforthepatentandknow-howfordevelopmentofthisimagingagent.

Contact: Irene Patzak, [email protected]

RALA

In Vivo Proof-of-Principle RALAisanovelcellpenetratingpeptidefordeliveringbiologiccargoesinsidecells.Comparedtoothertechnologiesinthefield,RALAischaracterisedbylowimmunogenicity,minimaltoxicityandhightransfectionefficiency.TheRALApeptide has been evaluated in several in vivoproof-of-conceptstudies,andisbestexemplifiedbythetherapeuticdeliveryoftheinduciblenitricoxidesynthasegeneinhighlyaggressivemodelsofmetastaticbreastandprostatecancer.InadditiontoDNA,RALAhasdemonstratedtheabilitytodeliversmallmolecules,RNAiandmRNAin vitro and in vivo.CRTiscurrentlyseekingpartnersforlicensingand/orcollaborativedevelopmentoftheRALApeptide,andwelcomesinterestinexploringalternativeapplicationsandpayloads.

Contact: Tassos Konstantinou, [email protected]

ENABLING TECHNOLOGY


Biological Fluid Filtration Device

Clinical testing Most patients with blood in the urine will undergo cystoscopy to rule out bladder cancer. Cystoscopy is the gold standard for bladder cancer diagnosis due to its high sensitivity and specificity. However, only ~10% of patients who undergoacystoscopyhavebladdercancerwithmanypatientsneedlesslyundergoingthisinvasiveandexpensivetest.InventorsattheDanishCancerSocietyhavedevelopedadiagnostic-compatibledevicefortheconcentrationand isolation of tumour cells found in urine. The device improves the sensitivity and specificity of molecular diagnosticsbasedtestperformedonisolatedtumourcells.CRTisnowworkingwithacommercialinvestorstobringthedevicetothemarketandisseekingpartnerswithin vitro diagnostic test in the uro-oncology space.

Contact: Matthew Farren, [email protected]

MEDICAL DEVICES


IBIS Software (Tyrer-Cuzick Model)

Risk/Predisposition TheTyrer-Cuzickmodelisabreastcancerriskassessmenttoolincorporatingfamilyhistory,endogenoushormonalfactors,benigndisease,riskfactorssuchasageandbodymassindex,aswellasgeneticfactors(includingBRCA)intoasinglestatisticalmodel.TheTyrer-Cuzickmodelhasbeenshowninindependentstudiestobethemostconsistentlyaccuratewhencomparedwithotheravailableriskassessmentmodels.Themodelhasbeenincorporatedintoacomputerprogramme,theIBISsoftwarethatgivesapersonalisedriskestimate.IBISisavailablefornon-exclusivelicensingforstand-aloneuseorforincorporationintobroadersoftwareplatforms.


S100A4 Neutralising Antibody for Inflammatory Diseases

In Vivo Proof-of-Principle S100A4isacalciumbindingproteinwhichhasbeenassociatedwithanumberofinflammatorydiseasessuchasrheumatoidarthritis,psoriasisandseasonalallergicrhinitis.CRT’smonoclonalmouseanti-S100A4antibodyhasahighaffinityforthetargetandisselectiveforS100A4overotherS100familymembers.Theantibodycomeswith in vivo proof of principle data generated in a mouse model of allergic dermatitis showing that it reverses some of the hallmarksofallergy.Thispotentialfirstinclasstherapyforinflammatorydiseasesisavailableforfurtherdevelopmentthrough licensing or collaboration.


NEW AND OTHER OPPORTUNITIES