2025
719-P: Oral Disposition Index (oDI) as an Outcome Measure in Type 1 Diabetes (T1D) Clinical Trials—Evidence from Stage 1 and Stage 2 Trials
GALDERISI A, CUTHBERTSON D, PETRELLI A, MORAN A, SOSENKO J, JACOBSEN L, LIBMAN I, REDONDO M, ISMAIL H. 719-P: Oral Disposition Index (oDI) as an Outcome Measure in Type 1 Diabetes (T1D) Clinical Trials—Evidence from Stage 1 and Stage 2 Trials. Diabetes 2025, 74 DOI: 10.2337/db25-719-p.Peer-Reviewed Original ResearchOral disposition indexC-peptide indexAUC C-peptideC-peptideMarkers of treatment effectivenessStage 1B cell functionYear of treatmentC-peptide measurementsType 1 diabetesPlacebo armMeasure of B-cell functionStage 2T1D prevention trialsTreatment responseTreated armClinical trialsDisposition indexSensitive markerPrevention trialsMetabolic endpointsLong-term effectsInsulin secretionOutcome measuresTeplizumabLatent EBV enhances the efficacy of anti-CD3 mAb in Type 1 diabetes
Lledó-Delgado A, Preston-Hurlburt P, Higdon L, Hu A, James E, Lim N, Long S, McNamara J, Nguyen H, Serti E, Sumida T, Herold K. Latent EBV enhances the efficacy of anti-CD3 mAb in Type 1 diabetes. Nature Communications 2025, 16: 5033. PMID: 40447640, PMCID: PMC12125364, DOI: 10.1038/s41467-025-60276-5.Peer-Reviewed Original ResearchConceptsCD8+ T cellsEBV-seropositive individualsType 1 diabetesT cellsImmune cellsAntigen-specific CD8+ T cellsDiagnosis of type 1 diabetesEBV-seronegative patientsEBV-seropositive patientsT cell activation pathwaysRegulatory T cellsAnti-CD3 mAbInnate immune cellsPeripheral blood cellsT cell receptorProgression of diseaseContext of type 1 diabetesImpaired signaling pathwaysTeplizumabClinical trialsLatent EBVBlood cellsSingle cell transcriptomicsModulate progressionMTOR signaling
2024
Trajectory of beta cell function and insulin clearance in stage 2 type 1 diabetes: natural history and response to teplizumab
Galderisi A, Sims E, Evans-Molina C, Petrelli A, Cuthbertson D, Nathan B, Ismail H, Herold K, Moran A. Trajectory of beta cell function and insulin clearance in stage 2 type 1 diabetes: natural history and response to teplizumab. Diabetologia 2024, 68: 646-661. PMID: 39560746, PMCID: PMC11832608, DOI: 10.1007/s00125-024-06323-0.Peer-Reviewed Original ResearchProgrammed death-1AUC C-peptideSlow progressorsRapid progressorsInsulin secretionInsulin clearanceC-peptideDisease-free survival ratesT effector memory cellsCD8+ T effector memory cellsNatural historyImpact of immunotherapyPlacebo-treated individualsT memory cellsBaseline insulin secretionBeta cell functionInterpreting clinical trialsLoss of insulin secretionDeath-1Elevated insulin secretionPlacebo-treatedTreatment armsTeplizumabClinical trialsDisposition indexThe Teplizumab Saga: The Challenge of Not Getting Lost in Clinical Translation.
Chatenoud L, Herold K, Bach J, Bluestone J. The Teplizumab Saga: The Challenge of Not Getting Lost in Clinical Translation. Cold Spring Harbor Perspectives In Medicine 2024, a041600. PMID: 39284671, DOI: 10.1101/cshperspect.a041600.Peer-Reviewed Original ResearchEvolving Concepts in Pathophysiology, Screening, and Prevention of Type 1 Diabetes: Report of Diabetes Mellitus Interagency Coordinating Committee Workshop.
Greenbaum C, Nepom G, Wood-Heickman L, Wherrett D, DiMeglio L, Herold K, Krischer J. Evolving Concepts in Pathophysiology, Screening, and Prevention of Type 1 Diabetes: Report of Diabetes Mellitus Interagency Coordinating Committee Workshop. Diabetes 2024, 73: 1780-1790. PMID: 39167668, PMCID: PMC11493760, DOI: 10.2337/dbi24-0020.Peer-Reviewed Original ResearchConceptsType 1 diabetesClinical trialsType 1 Diabetes TrialNetEtiology of type 1 diabetesImmune Tolerance NetworkFood and Drug AdministrationU.S. Food and Drug AdministrationNational Institute of DiabetesDigestive and Kidney DiseasesMultiple immune pathwaysDisease-modifying therapiesMechanism of actionTherapeutic responsePrognostic markerKidney diseaseDrug AdministrationTrialNetClinical diagnosisImmune pathwaysDiabetesTeplizumabRegulatory approvalClinical carePathophysiologyDiseaseTeplizumab induces persistent changes in the antigen‐specific repertoire in individuals at‐risk for type 1 diabetes
Lledó-Delgado A, Preston-Hurlburt P, Currie S, Clark P, Linsley P, Long S, Liu C, Koroleva G, Martins A, Tsang J, Herold K. Teplizumab induces persistent changes in the antigen‐specific repertoire in individuals at‐risk for type 1 diabetes. Journal Of Clinical Investigation 2024, 134: e177492. PMID: 39137044, PMCID: PMC11405034, DOI: 10.1172/jci177492.Peer-Reviewed Original ResearchCD8+ T cellsAutoreactive T cellsT cellsType 1 diabetesPeripheral blood CD8+ T cellsBlood CD8+ T cellsExpansion of autoreactive T cellsOperational toleranceExpression of CD127Progression of type 1 diabetesAnti-CD3 mAbAntigen-specific repertoireT cell receptorAt-risk patientsAnalysis of study participantsStudy participantsIL7R expressionTeplizumab groupCD8+Placebo groupCD4+Clinical respondersFree intervalTeplizumabReduced expression of genes155-OR: Genetic Variation and Time to Progression in TN10 (Teplizumab)
MICHALEK D, ONENGUT-GUMUSCU S, CHEN W, BRUSKO T, STECK A, GOTTLIEB P, ORAM R, KRISCHER J, PARIKH H, REDONDO M, HEROLD K, RICH S. 155-OR: Genetic Variation and Time to Progression in TN10 (Teplizumab). Diabetes 2024, 73 DOI: 10.2337/db24-155-or.Peer-Reviewed Original ResearchGenome-wide analysisTime to progressionInfluence time to progressionPolygenic scoresDrug response genesNon-HLA variantsGenome-wide arrayRandomized phase 2 clinical trialAssociated with time to progressionPhase 2 clinical trialProgression to type 1 diabetesCox proportional hazards regression modelsGenetic variationTn10Proportional hazards regression modelsGenetic modifiersHigh-risk participantsHazards regression modelsLociType 1 diabetesNovel pathwaysTeplizumab groupTeplizumabVitamin DImmune-relevant70-OR: PROTECT Per-Protocol Analysis—Preserving ß-Cell Function in Children and Adolescents with Newly Diagnosed Stage 3 Type 1 Diabetes (T1D)
HEROLD K, DAYAN C, CHATENOUD L, GITELMAN S, SUMNIK Z, SIMMONS K, SZYPOWSKA A, KNECHT L, NIEMOELLER E, TIAN W, RAMOS E. 70-OR: PROTECT Per-Protocol Analysis—Preserving ß-Cell Function in Children and Adolescents with Newly Diagnosed Stage 3 Type 1 Diabetes (T1D). Diabetes 2024, 73 DOI: 10.2337/db24-70-or.Peer-Reviewed Original ResearchIntent-to-treatInsulin doseFunction preservationPer-protocolIntent-to-treat populationß-cell functionAnti-CD3 mAbReduced insulin doseLower insulin doseSustained glycemic controlPP populationTeplizumabMetabolic outcomesPBO groupHbA1c levelsPP analysisGlycemic controlTreatment complianceDoseDelayed onsetRandomized participantsIncorrect treatmentInsulinWeeksTreatment728-P: Experience with Teplizumab in the PROTECT Type 1 Diabetes (T1D) Study during the COVID-19 Pandemic
GITELMAN S, HEROLD K, SIMMONS K, SUMNIK Z, KNECHT L, NIEMOELLER E, TIAN W, COMER G, MILLER D, RAMOS E. 728-P: Experience with Teplizumab in the PROTECT Type 1 Diabetes (T1D) Study during the COVID-19 Pandemic. Diabetes 2024, 73 DOI: 10.2337/db24-728-p.Peer-Reviewed Original ResearchPBO groupTeplizumab groupAnti-CD3 monoclonal antibodyStudy drug discontinuationRates of overall infectionHumanized anti-CD3 monoclonal antibodyIncidence of infectionType 1 diabetesAdministered 6 monthsDrug discontinuationImmunomodulatory therapyTeplizumabAntiviral treatmentModified doseStudy visitsOverall infectionProtocol deviationsMonoclonal antibodiesTreatment groupsInfectionTherapyAged 8COVID-19COVID-19 testingTreatmentReshaping immune cells and the antigen-specific repertoire by anti-CD3 mAb teplizumab in Type 1 diabetes
lledo delgado A, Preston-Hurlburt P, Currie S, Clark P, Herold K. Reshaping immune cells and the antigen-specific repertoire by anti-CD3 mAb teplizumab in Type 1 diabetes. The Journal Of Immunology 2024, 212: 0958_5059-0958_5059. DOI: 10.4049/jimmunol.212.supp.0958.5059.Peer-Reviewed Original ResearchCD8+ T cellsT cellsType 1 diabetesCD8+ T cell exhaustionAutoreactive CD8+ T cellsT cell exhaustionT cell changesCD8+ cellsProgression of type 1 diabetesAnti-CD3 mAbAntigen-specific repertoireAt-risk patientsCD8+CD4+Eomes expressionPeripheral bloodTeplizumabImmune cellsImmune regulationT1D diagnosisCD8Operational toleranceDelay progressionMonthsIndividuals at-riskComparisons of Metabolic Measures to Predict T1D vs Detect a Preventive Treatment Effect in High-Risk Individuals
Sims E, Cuthbertson D, Jacobsen L, Ismail H, Nathan B, Herold K, Redondo M, Sosenko J. Comparisons of Metabolic Measures to Predict T1D vs Detect a Preventive Treatment Effect in High-Risk Individuals. The Journal Of Clinical Endocrinology & Metabolism 2024, 109: 2116-2123. PMID: 38267821, PMCID: PMC11244203, DOI: 10.1210/clinem/dgae048.Peer-Reviewed Original ResearchSix-month changesPrevention trialsC-peptidePredicting diabetesMetabolic endpointsPreventive treatment effectsMetabolic measuresEffect of disease-modifying therapiesProportional hazards regressionTreatment effectsResponse to immunotherapyMeasurement of glucoseNatural history studiesPrevention StudyHazards regressionInclusion criteriaDisease-modifying therapiesT1D prevention trialsComparing placeboTreatment armsTeplizumabTrialNet PathwayHigh riskDetect treatment effectsCombined glucose
2023
Teplizumab and β-Cell Function in Newly Diagnosed Type 1 Diabetes
Ramos E, Dayan C, Chatenoud L, Sumnik Z, Simmons K, Szypowska A, Gitelman S, Knecht L, Niemoeller E, Tian W, Herold K. Teplizumab and β-Cell Function in Newly Diagnosed Type 1 Diabetes. New England Journal Of Medicine 2023, 389: 2151-2161. PMID: 37861217, DOI: 10.1056/nejmoa2308743.Peer-Reviewed Original ResearchConceptsC-peptide levelsB cell functionDiagnosed type 1 diabetesType 1 diabetesSecondary end pointsEnd pointsMild cytokine release syndromePeak C-peptide levelsMonoclonal antibodies to CD3Stimulated C-peptide levelsNewly diagnosed type 1 diabetesClinical type 1 diabetesCytokine release syndromePatients 8 yearsPlacebo-controlled trialPrimary end pointAntibodies to CD3Clinical end pointsAssociated with administrationPrevent disease progressionGlycated hemoglobin levelsFood and Drug AdministrationTarget glucose rangeT cellsTeplizumab
2019
An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes
Herold KC, Bundy BN, Long SA, Bluestone JA, DiMeglio LA, Dufort MJ, Gitelman SE, Gottlieb PA, Krischer JP, Linsley PS, Marks JB, Moore W, Moran A, Rodriguez H, Russell WE, Schatz D, Skyler JS, Tsalikian E, Wherrett DK, Ziegler AG, Greenbaum CJ. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. New England Journal Of Medicine 2019, 381: 603-613. PMID: 31180194, PMCID: PMC6776880, DOI: 10.1056/nejmoa1902226.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAntibodies, Monoclonal, HumanizedCD3 ComplexChildDiabetes Mellitus, Type 1Disease ProgressionDouble-Blind MethodExanthemaFemaleGlucose Tolerance TestHLA-DR3 AntigenHLA-DR4 AntigenHumansLymphocyte CountLymphopeniaMaleMiddle AgedProportional Hazards ModelsT-LymphocytesYoung AdultConceptsType 1 diabetesClinical type 1 diabetesTeplizumab groupPlacebo groupOral glucose tolerance testInsulin-producing beta cellsDouble-blind trialChronic autoimmune diseaseGlucose tolerance testRelatives of patientsRate of diagnosisHigh-risk participantsTransient lymphopeniaAdverse eventsHazard ratioHLA-DR3HLA-DR4Median timeClinical progressionAutoimmune diseasesExogenous insulinCD3 antibodyT cellsTeplizumabClinical disease
2012
Teplizumab treatment may improve C-peptide responses in participants with type 1 diabetes after the new-onset period: a randomised controlled trial
Herold KC, Gitelman SE, Willi SM, Gottlieb PA, Waldron-Lynch F, Devine L, Sherr J, Rosenthal SM, Adi S, Jalaludin MY, Michels AW, Dziura J, Bluestone JA. Teplizumab treatment may improve C-peptide responses in participants with type 1 diabetes after the new-onset period: a randomised controlled trial. Diabetologia 2012, 56: 391-400. PMID: 23086558, PMCID: PMC3537871, DOI: 10.1007/s00125-012-2753-4.Peer-Reviewed Original ResearchConceptsC-peptide responseType 1 diabetesImmune therapyHigh C-peptide responseCentral randomisation centreChronic autoimmune processPlacebo-treated participantsPlacebo-controlled trialPrimary outcome analysisC-peptide levelsCharacteristics of patientsSubgroup of patientsC-peptide productionTeplizumab groupClinical respondersAutoimmune processPrimary outcomeExogenous insulinMixed mealSubgroup analysisResultsThirty-fourInsulin secretionTreatment benefitBaseline imbalancesTeplizumab
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