2023
Function and Cryo-EM structures of broadly potent bispecific antibodies against multiple SARS-CoV-2 Omicron sublineages
Ren P, Hu Y, Peng L, Yang L, Suzuki K, Fang Z, Bai M, Zhou L, Feng Y, Zou Y, Xiong Y, Chen S. Function and Cryo-EM structures of broadly potent bispecific antibodies against multiple SARS-CoV-2 Omicron sublineages. Signal Transduction And Targeted Therapy 2023, 8: 281. PMID: 37518189, PMCID: PMC10387464, DOI: 10.1038/s41392-023-01509-1.Peer-Reviewed Original ResearchPolyvalent mRNA vaccination elicited potent immune response to monkeypox virus surface antigens
Fang Z, Monteiro V, Renauer P, Shang X, Suzuki K, Ling X, Bai M, Xiang Y, Levchenko A, Booth C, Lucas C, Chen S. Polyvalent mRNA vaccination elicited potent immune response to monkeypox virus surface antigens. Cell Research 2023, 33: 407-410. PMID: 36879038, PMCID: PMC9988199, DOI: 10.1038/s41422-023-00792-5.Peer-Reviewed Original ResearchMachine learning identifies T cell receptor repertoire signatures associated with COVID-19 severity
Park J, Lee K, Lam S, Moon K, Fang Z, Chen S. Machine learning identifies T cell receptor repertoire signatures associated with COVID-19 severity. Communications Biology 2023, 6: 76. PMID: 36670287, PMCID: PMC9853487, DOI: 10.1038/s42003-023-04447-4.Peer-Reviewed Original ResearchConceptsCOVID-19 disease severityT cell effector functionT cell receptor repertoireT cell clonal expansionT cell adaptive immune responsesCell effector functionsCOVID-19 patientsTCR repertoire analysisAdaptive immune responsesCell receptor repertoireCOVID-19 severityCOVID-19 infectionCell clonal expansionNF-kB signalingSARS-CoV-2TCR repertoireHealthy donorsImmune responseAntiviral immunityEffector functionsViral infectionHost responseDisease severityReceptor repertoireTCR sequencesRAMIHM generates fully human monoclonal antibodies by rapid mRNA immunization of humanized mice and BCR-seq
Ren P, Peng L, Yang L, Suzuki K, Fang Z, Renauer P, Lin Q, Bai M, Li T, Clark P, Klein D, Chen S. RAMIHM generates fully human monoclonal antibodies by rapid mRNA immunization of humanized mice and BCR-seq. Cell Chemical Biology 2023, 30: 85-96.e6. PMID: 36640761, PMCID: PMC9868106, DOI: 10.1016/j.chembiol.2022.12.005.Peer-Reviewed Original ResearchConceptsHuman monoclonal antibodyHumanized miceMonoclonal antibodiesMemory B cell populationsHumanized transgenic miceBroad antibody responseB cell populationsG protein-coupled receptor targetsNeutralizing antibodiesPeripheral bloodAntibody responseImmunotherapy targetClinical vaccinesPlasma BCell sequencingTransgenic miceImmunization methodReceptor targetsAntibodiesMiceCell populationsHigh potencyImmunizationHigh rateAntibody discovery
2022
Bivalent mRNA vaccine booster induces robust antibody immunity against Omicron lineages BA.2, BA.2.12.1, BA.2.75 and BA.5
Fang Z, Monteiro VS, Hahn AM, Grubaugh ND, Lucas C, Chen S. Bivalent mRNA vaccine booster induces robust antibody immunity against Omicron lineages BA.2, BA.2.12.1, BA.2.75 and BA.5. Cell Discovery 2022, 8: 108. PMID: 36220819, PMCID: PMC9552143, DOI: 10.1038/s41421-022-00473-4.Peer-Reviewed Original ResearchMultiplexed LNP-mRNA vaccination against pathogenic coronavirus species
Peng L, Fang Z, Renauer PA, McNamara A, Park JJ, Lin Q, Zhou X, Dong MB, Zhu B, Zhao H, Wilen CB, Chen S. Multiplexed LNP-mRNA vaccination against pathogenic coronavirus species. Cell Reports 2022, 40: 111160. PMID: 35921835, PMCID: PMC9294034, DOI: 10.1016/j.celrep.2022.111160.Peer-Reviewed Original ResearchConceptsAntibody responseCoronavirus speciesSequential vaccinationSARS-CoVAntigen-specific antibody responsesSARS-CoV-2 DeltaAdaptive immune cellsEffective immune responsePotent antibody responsesCOVID-19 vaccineSARS-CoV-2MRNA vaccine candidatesActivated B cellsSingle-cell RNA sequencing profilesRNA sequencing profilesSimultaneous vaccinationAntibody immunityVaccination scheduleImmune profileImmune cellsImmune responseVaccine candidatesMERS-CoV.Animal modelsB cellsHeterotypic vaccination responses against SARS-CoV-2 Omicron BA.2
Fang Z, Peng L, Lucas C, Lin Q, Zhou L, Yang L, Feng Y, Ren P, Renauer PA, Monteiro VS, Hahn AM, Park JJ, Zhou X, Grubaugh N, Wilen C, Chen S. Heterotypic vaccination responses against SARS-CoV-2 Omicron BA.2. Cell Discovery 2022, 8: 69. PMID: 35853867, PMCID: PMC9295082, DOI: 10.1038/s41421-022-00435-w.Peer-Reviewed Original ResearchOmicron-specific mRNA vaccination alone and as a heterologous booster against SARS-CoV-2
Fang Z, Peng L, Filler R, Suzuki K, McNamara A, Lin Q, Renauer PA, Yang L, Menasche B, Sanchez A, Ren P, Xiong Q, Strine M, Clark P, Lin C, Ko AI, Grubaugh ND, Wilen CB, Chen S. Omicron-specific mRNA vaccination alone and as a heterologous booster against SARS-CoV-2. Nature Communications 2022, 13: 3250. PMID: 35668119, PMCID: PMC9169595, DOI: 10.1038/s41467-022-30878-4.Peer-Reviewed Original ResearchConceptsHeterologous boosterSARS-CoV-2Antibody responseMRNA vaccinesMRNA vaccinationDelta variantOmicron variantType of vaccinationStrong antibody responseMRNA vaccine candidatesVaccine candidatesNeutralization potencyImmune evasionSARS-CoV.Two weeksComparable titersVaccinationVaccineTiters 10MiceOmicronWeeksWA-1LNP-mRNABoosterVariant-specific vaccination induces systems immune responses and potent in vivo protection against SARS-CoV-2
Peng L, Renauer PA, Ökten A, Fang Z, Park JJ, Zhou X, Lin Q, Dong MB, Filler R, Xiong Q, Clark P, Lin C, Wilen CB, Chen S. Variant-specific vaccination induces systems immune responses and potent in vivo protection against SARS-CoV-2. Cell Reports Medicine 2022, 3: 100634. PMID: 35561673, PMCID: PMC9040489, DOI: 10.1016/j.xcrm.2022.100634.Peer-Reviewed Original ResearchConceptsImmune responseImmune cell populationsSARS-CoV-2 spikeAssessment of efficacySARS-CoV-2LNP-mRNABreakthrough infectionsCD8 TImmune profilingMRNA vaccinesPotent protectionT lymphocytesNeutralization activityDelta variantAnimal modelsPotent antibodiesRepertoire diversityCell responsesAuthentic virusSystemic increaseVariant lineagesClonal expansionCell populationsCOVID-19VaccinationMonospecific and bispecific monoclonal SARS-CoV-2 neutralizing antibodies that maintain potency against B.1.617
Peng L, Hu Y, Mankowski MC, Ren P, Chen RE, Wei J, Zhao M, Li T, Tripler T, Ye L, Chow RD, Fang Z, Wu C, Dong MB, Cook M, Wang G, Clark P, Nelson B, Klein D, Sutton R, Diamond MS, Wilen CB, Xiong Y, Chen S. Monospecific and bispecific monoclonal SARS-CoV-2 neutralizing antibodies that maintain potency against B.1.617. Nature Communications 2022, 13: 1638. PMID: 35347138, PMCID: PMC8960874, DOI: 10.1038/s41467-022-29288-3.Peer-Reviewed Original ResearchConceptsSARS-CoV-2Authentic SARS-CoV-2Effective therapeutic optionPotent SARS-CoV-2SARS-CoV-2 variantsVariants of concernRepertoire of therapeuticsBreakthrough infectionsTherapeutic optionsMultiple vaccinesPathogen SARS-CoV-2Delta variantB cellsPotent efficacyHumanized antibodyDistinct epitopesBispecific antibodiesOriginal virusSpike receptorStrong inhibitory activityMonoclonal antibodiesAntibodiesStrong potencyLead clonesLead antibodiesGenomic Correlates of Unfavorable Outcome in Locally Advanced Cervical Cancer Treated with Neoadjuvant Chemoradiation
Wei Y, Wei C, Chen L, Liu N, Ou Q, Yin J, Pang J, Fang Z, Wu X, Wang X, Mu D, Shao Y, Yu J, Yuan S. Genomic Correlates of Unfavorable Outcome in Locally Advanced Cervical Cancer Treated with Neoadjuvant Chemoradiation. Cancer Research And Treatment 2022, 54: 1209-1218. PMID: 35038823, PMCID: PMC9582489, DOI: 10.4143/crt.2021.963.Peer-Reviewed Original ResearchConceptsDisease-free survivalAdvanced cervical cancerAdvanced cervical cancer patientsCervical cancer patientsTumor biopsy samplesCervical cancerNeoadjuvant chemoradiationPathologic responseCancer patientsKEAP1 mutationsHigh tumor mutation burdenNeoadjuvant chemoradiation treatmentPoor pathologic responseEarly disease recurrenceTumor mutation burdenGenetic alterationsDNA damage repair genesOperability rateChemoradiation treatmentNeoadjuvant therapyNeoadjuvant treatmentRadical hysterectomyCancer Genome AtlasDisease recurrenceDisease relapse
2021
Lung Cancer Driven by BRAFG469V Mutation Is Targetable by EGFR Kinase Inhibitors
Huo K, Notsuda H, Fang Z, Liu N, Gebregiworgis T, Li Q, Pham N, Li M, Liu N, Shepherd F, Marshall C, Ikura M, Moghal N, Tsao M. Lung Cancer Driven by BRAFG469V Mutation Is Targetable by EGFR Kinase Inhibitors. Journal Of Thoracic Oncology 2021, 17: 277-288. PMID: 34648945, DOI: 10.1016/j.jtho.2021.09.008.Peer-Reviewed Original ResearchConceptsEGFR tyrosine kinase inhibitorsTyrosine kinase inhibitorsLung cancerBRAF mutationsNon-small cell lung cancerNon-V600 BRAF mutationsPatient-derived xenograft modelsKinase inhibitorsCell lung cancerEGFR-TKI gefitinibSingle-agent vemurafenibV600E BRAF mutationRNA knockdownCell linesExpression of BRAFOff-target inhibitionCombination dabrafenibTKI gefitinibTargeted therapyLung adenocarcinomaXenograft modelEGFR kinase inhibitorsPatientsOncogenic driversBRAFGenomic profiling of biliary tract cancers to reveal clinically actionable genes and therapeutic biomarkers.
Shao Y, Ou Q, Fang Z, Liu R, Bao H, Wu X. Genomic profiling of biliary tract cancers to reveal clinically actionable genes and therapeutic biomarkers. Journal Of Clinical Oncology 2021, 39: e16187-e16187. DOI: 10.1200/jco.2021.39.15_suppl.e16187.Peer-Reviewed Original ResearchTumor mutation burdenMicrosatellite instability statusGallbladder cancerTelomeric allelic imbalanceBTC patientsDistal cholangiocarcinomaPerihilar cholangiocarcinomaTract cancerIntrahepatic cholangiocarcinomaCancer patientsBiliary tract cancer patientsHigh tumor mutation burdenDNA damage repair pathway genesImpaired mismatch repairBiliary tract cancerHomologous recombination repairPoly (ADP-ribose) polymerase (PARP) inhibitorsDDR gene alterationsTumor tissue samplesMismatch repairBase excision repair genesBTC subtypesHRR mutationsClinical outcomesPoor prognosis
2020
NMR in integrated biophysical drug discovery for RAS: past, present, and future
Marshall C, KleinJan F, Gebregiworgis T, Lee K, Fang Z, Eves B, Liu N, Gasmi-Seabrook G, Enomoto M, Ikura M. NMR in integrated biophysical drug discovery for RAS: past, present, and future. Journal Of Biomolecular NMR 2020, 74: 531-554. PMID: 32804298, DOI: 10.1007/s10858-020-00338-6.Peer-Reviewed Original ResearchConceptsGTPase domainProper membrane localizationMultiple signaling cascadesOncogenic Ras mutationsKey downstream effectorDrug discoveryGTPase cycleMembrane localizationRAS proteinsGTP hydrolysisConformational selectionRAS signalingDownstream effectorsSignaling cascadesLipid modificationG12C mutantUpstream regulatorBiophysical approachesSmall proteinsRAS oncogenesDruggable pocketHuman cancersCell growthCovalent inhibitorsPeptidyl inhibitorsMultivalent assembly of KRAS with the RAS-binding and cysteine-rich domains of CRAF on the membrane
Fang Z, Lee K, Huo K, Gasmi-Seabrook G, Zheng L, Moghal N, Tsao M, Ikura M, Marshall C. Multivalent assembly of KRAS with the RAS-binding and cysteine-rich domains of CRAF on the membrane. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 12101-12108. PMID: 32414921, PMCID: PMC7275734, DOI: 10.1073/pnas.1914076117.Peer-Reviewed Original ResearchConceptsRas-binding domainCysteine-rich domainC-terminusΑ4-α5Transient electrostatic interactionsLipid-binding siteCancer-associated mutationsMembrane interfaceKRAS dimerizationMembrane anchoringMembrane associationKinase domainRaf kinaseMembrane complexPlasma membraneStructural insightsKinase activityMAPK signalingTerminusComplex formationMembraneDynamic interactionDynamic pictureComplexesDomainTwo Distinct Structures of Membrane‐Associated Homodimers of GTP‐ and GDP‐Bound KRAS4B Revealed by Paramagnetic Relaxation Enhancement
Lee K, Fang Z, Enomoto M, Gasmi‐Seabrook G, Zheng L, Koide S, Ikura M, Marshall C. Two Distinct Structures of Membrane‐Associated Homodimers of GTP‐ and GDP‐Bound KRAS4B Revealed by Paramagnetic Relaxation Enhancement. Angewandte Chemie 2020, 132: 11130-11138. DOI: 10.1002/ange.202001758.Peer-Reviewed Original ResearchKRAS dimerizationParamagnetic relaxation enhancement NMR spectroscopyStructural basisΑ4-α5 interfaceEffector-binding siteParamagnetic relaxation enhancementActive GTPRaf activationSmall GTPasesRaf kinaseDistinct structuresGTPDimerizationRelaxation enhancementKRAS4bGTPasesE168R135ActivationKinaseProtomersHomodimerNanodiscsNMR spectroscopyTwo Distinct Structures of Membrane‐Associated Homodimers of GTP‐ and GDP‐Bound KRAS4B Revealed by Paramagnetic Relaxation Enhancement
Lee K, Fang Z, Enomoto M, Gasmi‐Seabrook G, Zheng L, Koide S, Ikura M, Marshall C. Two Distinct Structures of Membrane‐Associated Homodimers of GTP‐ and GDP‐Bound KRAS4B Revealed by Paramagnetic Relaxation Enhancement. Angewandte Chemie International Edition 2020, 59: 11037-11045. PMID: 32227412, PMCID: PMC7395670, DOI: 10.1002/anie.202001758.Peer-Reviewed Original ResearchConceptsKRAS dimerizationParamagnetic relaxation enhancement NMR spectroscopyStructural basisΑ4-α5 interfaceEffector-binding siteParamagnetic relaxation enhancementActive GTPRaf activationSmall GTPasesDistinct structuresRaf kinaseGTPDimerizationRelaxation enhancementKRAS4bGTPasesR135E168ActivationKinaseProtomersHomodimerNanodiscsNMR spectroscopyMembrane
2018
MA27.07 Lung Adenocarcinoma Harboring BRAF G469V Mutation is Uniquely Sensitive to EGFR Tyrosine Kinase Inhibitors
Notsuda H, Pham N, Li M, Liu N, Raghavan V, Fang Z, Marshall C, Moghal N, Ikura M, Tsao M. MA27.07 Lung Adenocarcinoma Harboring BRAF G469V Mutation is Uniquely Sensitive to EGFR Tyrosine Kinase Inhibitors. Journal Of Thoracic Oncology 2018, 13: s456. DOI: 10.1016/j.jtho.2018.08.552.Peer-Reviewed Original ResearchInhibition of K-RAS4B by a Unique Mechanism of Action: Stabilizing Membrane-Dependent Occlusion of the Effector-Binding Site
Fang Z, Marshall C, Nishikawa T, Gossert A, Jansen J, Jahnke W, Ikura M. Inhibition of K-RAS4B by a Unique Mechanism of Action: Stabilizing Membrane-Dependent Occlusion of the Effector-Binding Site. Cell Chemical Biology 2018, 25: 1327-1336.e4. PMID: 30122370, DOI: 10.1016/j.chembiol.2018.07.009.Peer-Reviewed Original ResearchMultiplexed Real-Time NMR GTPase Assay for Simultaneous Monitoring of Multiple Guanine Nucleotide Exchange Factor Activities from Human Cancer Cells and Organoids
Gebregiworgis T, Marshall C, Nishikawa T, Radulovich N, Sandí M, Fang Z, Rottapel R, Tsao M, Ikura M. Multiplexed Real-Time NMR GTPase Assay for Simultaneous Monitoring of Multiple Guanine Nucleotide Exchange Factor Activities from Human Cancer Cells and Organoids. Journal Of The American Chemical Society 2018, 140: 4473-4476. PMID: 29543440, DOI: 10.1021/jacs.7b13703.Peer-Reviewed Original ResearchConceptsGuanine nucleotide exchange factorsRhoA-specific Guanine Nucleotide Exchange FactorGuanine nucleotide exchange factor activityNucleotide exchange factor activityHigher GEF activityNucleotide exchange factorsImportant cellular functionsExchange factor activityExchange of GTPProtein of interestReal-time NMRRNA-seq dataCultured human cellsGEF assaysHuman cancer cellsSmall GTPasesExchange factorGEF activityCellular functionsIsotopic labeling schemesNucleotide exchangeGEF-H1GTPase assaysFunctional analysisHuman cells