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( 12 ) Patent Application Publication ( 10 ) Pub . No .: US 2020/0331966 A1 STOVER Et Al

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( 12 ) Patent Application Publication ( 10 ) Pub . No .: US 2020/0331966 A1 STOVER Et Al US 20200331966A1 IN ( 19 ) United States ( 12 ) Patent Application Publication ( 10 ) Pub . No .: US 2020/0331966 A1 STOVER et al . ( 43 ) Pub . Date : Oct. 22 , 2020 ( 54 ) FUSION PROTEIN COMPOSITION ( S ) Related U.S. Application Data COMPRISING MASKED TYPE I INTERFERONS ( IFNA AND IFNB ) FOR USE ( 60 ) Provisional application No. 62 / 920,140 , filed on Apr. IN THE TREATMENT OF CANCER AND 15 , 2019 . METHODS THEREOF Publication Classification ( 71 ) Applicant: Qwixel Therapeutics, Los Angeles, CA ( 51 ) Int. Ci . ( US ) CO7K 7/08 ( 2006.01 ) A61K 47/65 ( 2006.01 ) ( 72 ) Inventors : David STOVER , Encino, CA (US ) ; A61P 35/00 ( 2006.01 ) Sherie MORRISON , Los Angeles, CA ( 52 ) U.S. CI . ( US ) ; Alex VASUTHASAWAT , Los CPC CO7K 7/08 ( 2013.01 ) ; A61K 38/00 Angeles , CA ( US ) ; Kham TRINH , ( 2013.01 ) ; A61P 35/00 ( 2018.01 ) ; A61K 47/65 Porter Ranch , CA ( US ) ; George ( 2017.08 ) AYOUB , Los Angeles, CA ( US ) ( 57 ) ABSTRACT Fusion Protein compositions comprising masked IFNs and ( 73 ) Assignee : Qwixel Therapeutics, Los Angeles, CA methods of making masked IFNs are disclosed herein . ( US ) Consequently, the masked IFNs can be fused to a Mab or binding fragment thereof and be administered to patients as ( 21 ) Appl. No .: 16 /849,889 a therapeutic modality and provide a method of treating cancer, immunological disorders and other disease . ( 22 ) Filed : Apr. 15 , 2020 Specification includes a Sequence Listing . Matripase ST 14 Cleaves an IFN Mask from the Heavy Chain of an anti CD138 Fusion Ab . 1 2 3 1. ant - CD138 / Na 2. anti - C0138 IFNa mask 3. anti - C0138 FNa mask w / MST14 Patent Application Publication Oct. 22 , 2020 Sheet 1 of 32 US 2020/0331966 A1 3.anti-CD138IFNamaskw/MST14 2.anti-CD138IFNamask antitheHeavyChainofanCleavesIFNMaskfromMatripaseST14 IFNa1.anti-CD138 123 HChain Ab.CD138Fusion 1Figure Patent Application Publication Oct. 22 , 2020 Sheet 2 of 32 US 2020/0331966 A1 3.anti-CD138IFNamaskN297QW/MST14 2.anti-CD138IFNamaskN2970 1.anti-CD138IFNA HeavyChainOfanantiMatripaseST14CleavesIFNMaskfromthe 123 aglycosylatedFusionAb.N2970)CD138( Figure2 Patent Application Publication Oct. 22 , 2020 Sheet 3 of 32 US 2020/0331966 A1 4.anti-mesothelinIFNamaskw/MST14 2,anti-ST4IFNamaskw/MST14 IFNamask3.anti-mesothelin mask5T4FNa1.anti- 5.anti-CD138IFNG anti-5T4MaskfromtheHeavyChainofanMatripaseST14CleavesIFN UN FusionAbandanti-mesothelin. Figure3 Patent Application Publication Oct. 22 , 2020 Sheet 4 of 32 US 2020/0331966 A1 ant-mesothelinIgG1IFNamask ant-5T4IgG1FNamask IFNa2Receptorwithreducedaffinityrelativetounmaskedfusionprotein Maskedanti-5T4FusionAbsandmesothelinBind IFNAR2binding 1 0.1 0.01 Figure4 Patent Application Publication Oct. 22 , 2020 Sheet 5 of 32 US 2020/0331966 A1 Maskedanti-CD20FusionAbsandCD138BindIFNa2 tounmaskedfusionproteinsReceptorwithreducedaffinityrelative IFNAR2binding:Non-linearFit Figure5 Patent Application Publication Oct. 22 , 2020 Sheet 6 of 32 US 2020/0331966 A1 mbarytonAnti-CD138maskedIFNawloMST14 W/MST14andAnti-CD138maskedIFNA CD138FNaQwixelanti-miline hFNa MaskingReducesIFNaFusionProteinActivationofIFNReceptor;while *TwiceasmuchhIFNawasusedforeachAbconcentrationinordertoaccountthe2IFNson 2 eachAb.CellsweretreatedO/NSupernatantsassayedwithQuanti-Bluereagent APactivityinKEK-BlueIFNabresponsetoIFNa 0 LogAb[PM] MST14RestoresActivity. 2 0.8 0.400 0.22 0.0 6Figure 630nm Abs Patent Application Publication Oct. 22 , 2020 Sheet 7 of 32 US 2020/0331966 A1 MethodsofReducingandRestoringmaskedIFNaActivity 0 0.2 (A) (B) 7Figure Patent Application Publication Oct. 22 , 2020 Sheet 8 of 32 US 2020/0331966 A1 maskiUST14hiiNa w mask sottolin HIFNe ante Minesothoin nM 0.15 0.15 InductionofIP-10inHumanPeripheralBloodMononuclearCells("PMBC) MST14maskhifNa w Namask esothelin h -mesaihoinanti 1.50M -ami nt 1.5 FLISNmaskNo hi seuantk514 DNS2.1990e DM 0.16 Nugl0 NST14w mask DIFNa 5T anti ut 1.5 DifNamask4:57 -ant nN 1.5 Figure8 Patent Application Publication Oct. 22 , 2020 Sheet 9 of 32 US 2020/0331966 A1 Antibody:Anti-CD138IgG1IFNa2-peptide(QXL138AM)OROD Gamma1HumanIsotype:ChainHeavy LightChainIsotype:HumanKappa QXL138AM:ConstructDesign LAVRKYEORIILYLKEKKYSPCAWEVVRAEIMRSFSLSTNLIOGVGVIETPLMKEDSI 17)IDNO:(SEQ Sequence: 9Figure MDPKGSLSWRILLELSLAFELSYGQVQLQQSGSELMMPGASVKISCKATGYTF'SNYWI EWVKORPGHGLEWIGEILPGTGRTIYNEKFKGKATFTADISSNTVQMOLSSLTSEDSA VYYCARRDYYGNFYYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLOSSGLYSLSSVVTVPSSSLGTQTYICNVN HKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTOKSLSLSPGSGGGGSCDLPQTHSLGSRRTLMLLAQMRRISLFSCLKDRHDFGFPQEEFGNOFOKAETIPVLHEMIQQIFNLESTKDSSAAWDETLLDKFYTELYOOLNDLEACV QESLRSKEGSSGLSGRSDNHGSSGGSGGSGGSGTDVDYYREWSWTOVSGG Patent Application Publication Oct. 22 , 2020 Sheet 10 of 32 US 2020/0331966 A1 CharacterizationPurificationExpression/QXL138AM: CESDSElectropherogramReducing: 10Figure 23 Patent Application Publication Oct. 22 , 2020 Sheet 11 of 32 US 2020/0331966 A1 ten 956.4Da)HasO-glycan(+ 002 QXL138AMAnalysis:ofHeavyandLightChainbyMassSpectrometer 23414.9 MeasuredM.W.(Da) 70000 1 Figure11 0 2 Patent Application Publication Oct. 22 , 2020 Sheet 12 of 32 US 2020/0331966 A1 4.Anti-C020IgG1maskedFNaLot2w/MST14 markerA.PageMarkermolecularweight 3.Anti-CD20IgG1maskedFNaLot2 7.Ant-CD138lgG1maskedFNaLot1 1.Anti-CD138IgG1Lot1 *SamplestreatedwMST14wereincubatedinOPBSW-125ngfor15'@37deg.C. 8 QXL138AM:CharacterizationbySDS-Page 6 4 2 1 12Figure Patent Application Publication Oct. 22 , 2020 Sheet 13 of 32 US 2020/0331966 A1 CharacterizationofMaskedFusionAbsbySDS-Page (B) 13Figure (A) Patent Application Publication Oct. 22 , 2020 Sheet 14 of 32 US 2020/0331966 A1 24.99 1.33 2.08 Bmax 2.58 2.59 -GSGTOVDYYREWSWTOVSBiotin)Peptide1:( FNACHYSant-CSPG4 IFNONS138-CDant FNBC178CD20-ani CSPG4FNBC17Sant- FNfusionAbsboundtoPeptide1 ELISAMaskbyAbsFusiontoBindingof IFNfusionAbsboundtoPeptide 2.0 14Figure (A) (B) Patent Application Publication Oct. 22 , 2020 Sheet 15 of 32 US 2020/0331966 A1 Althoughtheacleartargetingadvantageseenbetweentargetedvs.non-fusionAD. CharacterizationofTargetedFusionAbsversusNon- lesseffectivethantheunmaskedfusionAb.differenceissiral,itappearsraskedFNa Conclusion:TargetedfusionAbappearstobemoreeffectivethannon-targeted. 2 15Figure (A) (B) Patent Application Publication Oct. 22 , 2020 Sheet 16 of 32 US 2020/0331966 A1 Ab.Italsobetweentargetedvs.non-fusionacleartargetingadvantageseen CharacterizationofTargetedFusionAbsversusNon- version,cleavedthethaneffectivelessismaskedAbtheappears * among 2 2 mwen 16Figure 20 A)( (B) Patent Application Publication Oct. 22 , 2020 Sheet 17 of 32 US 2020/0331966 A1 MST14-E-Anti-CD138maskedFNaW/O MST14Anti-CD138maskedFNaW Qwixelanti-CD138FNa *TwiceasmuchhfNawasusedforeachAbconcentrationinordertoaccountthe2IFNson angunanananananang 32} CellProliferationRemovaloftheIFNMaskRestoresInhibition DaudiMTS gruang LogAbIPM -2 40, 20 0 807 60 eachAb. 17Figure proliferation % Patent Application Publication Oct. 22 , 2020 Sheet 18 of 32 US 2020/0331966 A1 InducedReductionTargetIFNa-FacilitateinOffMaskingTargetingandAb 2 DaudiMTS »2 100 18Figure Cytotoxicity (A) (B) Patent Application Publication Oct. 22 , 2020 Sheet 19 of 32 US 2020/0331966 A1 FNawagenCD20masked TumorCellLineCytotoxicityofMasked/Unmasked&TargetedNon- yaranayanangnaturezaearrangerer 2 20 19Figure FusionAbs (A) (B) Patent Application Publication Oct. 22 , 2020 Sheet 20 of 32 US 2020/0331966 A1 FNammCD20 mCD138FNa TumorCellLineCytotoxicityofMasked/Unmasked&TargetedNon- 2 2 MTSOCIMy5.5- nananananananananananananananananananahananandamananmananahan)danmanaBanananananana SIW6ZOH 2 20Figure AbsFusion (A) (B) Patent Application Publication Oct. 22 , 2020 Sheet 21 of 32 US 2020/0331966 A1 0.369 0022 5.5 PBMCsActivationofIFNRReducesMasking 21Figure (A) Patent Application Publication Oct. 22 , 2020 Sheet 22 of 32 US 2020/0331966 A1 1.5nM hoooo 0.15nM PBMCsActivationofIFNRReducesMasking5 MM 22Figure 00000 Patent Application Publication Oct. 22 , 2020 Sheet 23 of 32 US 2020/0331966 A1 anti-C020FNa MaskFNa-CD20antiobedom anti-C020FNaMask oCD20- IFNaWTwo onlineProtease LogAbIPM ? (B) 0 2 2 QXL138AMFunctionalStudiesInVitro:QXL138A& 0 PMLogAb( +QXL138AM doQXL138A OXL138AM Protease 2 23Figure (A) Patent Application Publication Oct. 22 , 2020 Sheet 24 of 32 US 2020/0331966 A1 TOFW100ugAvg maskedTOFW100ugAvg IGNO2100ugAvg maskedIGNO2Avg100ugwith PBSAvg QXL138A&QXL138AM:InVivoEfficacyinHumanMyelomaXenograft(H929) GrowthTumorAvgH929 Days 1.0 0.5 area Tumor 24Figure Patent Application Publication Oct. 22 , 2020 Sheet 25 of 32 US 2020/0331966 A1 CD20-1FNa2(300ug) voetCD20-IFNa2Mask(300ug) withQXL138A(300ug) www.gooQXL138AM(300ug) PBS QXL138A&QXL138AM:InVivoEfficacyinHumanMyelomaXenograft(H929) 80 GrowthTumorH929Avg Days 20 0 1 0.5 area Tumor 25Figure Patent Application Publication Oct. 22 , 2020 Sheet 26 of 32 US 2020/0331966 A1 kgCD138A0.38mg/Bort+5mg CD138AM5mg/kg0.38mgBort* CD138Akg5mg/ kgBort0.38mg/ PBS treatedi.vday14,16,18 40 QXL138AShowsSynergiesWithStandardofCareTreatment(bortezomib)in F 30 MM1-144 Days 1.0 0.07 26Figure Myeloma area Tumor Patent Application Publication Oct. 22 , 2020 Sheet 27 of 32 US 2020/0331966 A1 TOFW100ugBortAvg*3ug TOFW100ug7,5ugBort+Avg TOFW100ugAvg treatedi,vday14,16,18 PBSAvg Bortezomib3ugAvg Bortezomib7.5ugAvg QXL138AShowsSynergiesWithStandardofCareTreatment(bortezomib)in 60 ????????????????? H929 Days 0.0 area Tumor 27Figure Myeloma Patent Application Publication
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