A Phase 1 Clinical Trial of Siltuximab for the Treatment of Antibody-Mediated Rejection after Lung Transplantation
Siltuximab 治疗肺移植后抗体介导的排斥反应的 1 期临床试验
基本信息
- 批准号:10714920
- 负责人:
- 金额:$ 37.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-15 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAdrenal Cortex HormonesAffinityAllograftingAntibodiesAntibody FormationAntibody TherapyAntithymoglobulinB cell differentiationBindingBiologicalC-reactive proteinCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCause of DeathCell CountCell ProliferationCellsCessation of lifeCharacteristicsChronicClinicalClinical TrialsClinical Trials DesignCollagenCommunitiesConduct Clinical TrialsDataDevelopmentDiagnosisDoseEndothelial CellsEquilibriumExperimental ModelsFailureFibroblastsFunctional disorderFutureGastroesophageal reflux diseaseHLA AntigensHelper-Inducer T-LymphocyteHumanIL2RA geneIL2RB geneImmunoglobulin GImmunoglobulinsImmunosuppressive AgentsIncidenceIndividualInfectionInflammatoryInflammatory ResponseInterleukin 6 ReceptorInterleukin-2Interleukin-6Intravenous ImmunoglobulinsKidneyKidney TransplantationLinkLungLung TransplantationLung diseasesMeasurementMeasuresMembraneMemoryMemory B-LymphocyteMonitorMonoclonal AntibodiesMulticenter StudiesMulticentric Angiofollicular Lymphoid HyperplasiaMusMyofibroblastOutcomePathogenesisPatientsPersonsPharmaceutical PreparationsPharmacodynamicsPhasePhase I Clinical TrialsPhase II Clinical TrialsPhenotypePlacebosPlasma ExchangePlasmablastPlayPreventionProductionRandomized, Controlled TrialsReceptor InhibitionRecurrenceRefractoryRegimenRegulatory T-LymphocyteReportingRoleSafetyScheduleSerious Adverse EventSignal TransductionSmooth Muscle MyocytesSpecificityTestingTherapeuticTherapeutic immunosuppressionTransplant RecipientsUnited States Food and Drug AdministrationVascular Smooth MuscleViral Respiratory Tract Infectionallograft rejectionantibody-mediated rejectioncell free DNAcytokinedesigndonor-specific antibodyefficacy evaluationefficacy studyexperienceimprovedimproved outcomeinfection riskinterleukin-21lung allograftlung injurymortalitynovelpreventprimary endpointprospectivereceptorresponserituximabsafety assessmentsafety testingsecondary endpointstandard of care
项目摘要
PROJECT SUMMARY/ABSTRACT
Long-term outcomes after lung transplantation remain disappointing, and the median survival is 6.7 years.
Chronic lung allograft dysfunction (CLAD) is the leading cause of death beyond the first year after lung
transplantation. Antibody-mediated rejection (AMR), which is increasingly recognized after lung transplantation,
is caused by donor-specific antibodies (DSA) to mismatched human leukocyte antigens (HLA) and frequently
results in CLAD and death. Recent multicenter studies using intensive monitoring for AMR report an incidence
over 25%. Treatment for AMR has generally focused on antibody-depletion and prevention of additional antibody
development. Various combinations have been used including high-dose corticosteroids, intravenous immune
globulin (IVIG), Rituximab, Carfilzomib, anti-thymocyte globulin (ATG), and plasma exchange (PLEX). However,
there have been no randomized controlled trials to guide management, and outcomes after AMR are dismal.
One-year allograft survival after AMR is approximately 50%, and 2-year survival is only 20%. IL-6, initially
identified as B-cell stimulating factor 2 (BSF-2), is a pleiotropic cytokine that drives deleterious inflammatory,
alloimmune, and fibrogenic responses. In conjunction with other cytokines, IL-6 is responsible for normal
antibody production and is critical for the induction of follicular helper T-cells as well as the production of IL-21
which regulates immunoglobulin synthesis. IL-6 is also crucial for B-cell differentiation into plasmablasts and for
enhancing plasmablast survival. These characteristics make IL-6 an especially attractive cytokine to target in
the management of AMR. Human studies examining the role of IL-6 signaling blockade in the management of
AMR after kidney transplantation have shown promising results, even in refractory cases. We have used IL-6
signaling blockade in a very small number of lung transplant recipients with AMR at our center with encouraging
results. Our principal hypothesis is that IL-6 signaling blockade added to routine immunosuppressive treatment
for AMR would improve clinical outcomes. However, evaluating the safety of this approach is necessary before
examining efficacy in larger clinical trials because infections are the most common serious adverse events
associated with IL-6 signaling blockade and a common cause of death at all timepoints after lung transplantation.
Thus, we propose a Phase 1 clinical trial using Siltuximab, a monoclonal antibody to IL-6, in addition to routine
immunosuppressive therapy for AMR to examine safety and define the optimal dose for the treatment of AMR.
The primary endpoint is safety and tolerability, and secondary endpoints include pharmacodynamics and
functional biological measures relevant to AMR (e.g., DSA, cell-free DNA). Data from this trial will inform the
design of a future Phase 2 clinical trial that assesses efficacy. Carefully designed and implemented clinical trials
are necessary to improve outcomes after lung transplantation.
项目总结/文摘
项目成果
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Derek E Byers其他文献
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