Extended half-life GlyTR1 combined with checkpoint blockade for Cancer Immunotherapy
延长半衰期的 GlyTR1 与检查点阻断相结合用于癌症免疫治疗
基本信息
- 批准号:10766646
- 负责人:
- 金额:$ 40万
- 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:2023-09-21 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAntibodiesAntigen TargetingAntigensB-Cell NeoplasmB-LymphocytesBindingBinding ProteinsBiological AssayBispecific AntibodiesBiteCD3 AntigensCTLA4 geneCancer CenterCancer PatientCarbohydratesCell Surface ProteinsCell surfaceCellsClinical TrialsCombined Modality TherapyComplexDataDetectionDevelopmentDiseaseDisease ProgressionDoseDrug KineticsFDA approvedFc domainFundingFutureHalf-LifeHumanImmuneImmune checkpoint inhibitorImmune systemImmunoglobulin FragmentsImmunosuppressive AgentsImmunotherapeutic agentImmunotherapyIn VitroIntravenous infusion proceduresInvadedInvestigational TherapiesLectinMalignant NeoplasmsMetastatic/RecurrentNational Cancer InstituteNational Cancer ProgramNeoplasm MetastasisNormal CellNormal tissue morphologyPatientsPhasePhase I Clinical TrialsPhosphatidylinositolsPhosphotransferasesPolysaccharidesPrognosisProteinsReceptor Protein-Tyrosine KinasesRefractoryRegulatory T-LymphocyteRelapseSafetySequential TreatmentSerumSignal PathwaySignal TransductionSolidSolid NeoplasmSpecificitySurfaceSurface AntigensT-Cell ActivationT-Cell ReceptorT-LymphocyteTechnologyTestingTherapeuticTimeToxic effectTransgenic MiceTumor AntigensWorkbi-specific T cell engagercancer cellcancer immunotherapycell motilitycostdriver mutationfirst-in-humanhumanized mouseimmune checkpoint blockadein vitro activityin vivomanufacturemouse modelneonatal Fc receptorneonatal humannew technologynovelnovel therapeuticsoverexpressionpalliativephase I trialpre-clinicalpreclinical developmentpreventprogrammed cell death protein 1programssafety assessmentstable cell linesugartumor growth
项目摘要
Abstract
Treatment of non-resectable recurrent/metastatic solid cancers is currently palliative only and there is an
urgent unmet need for novel mechanisms of action and additional paradigm shifting therapeutic options. Antigen-
targeting cancer immunotherapies such as bi-specific antibodies (eg Bi-specific T cell engager or BiTE’s) provide
a unique approach for cancer immunotherapy. However, applying this therapeutic tactic to solid cancers has
been restricted by a limited number of protein antigens safe for targeting. Moreover, even if safe cell-surface
antigens are identified, different bi-specific antibodies will likely be needed for each different antigen/cancer. This
would greatly increase development time and costs. Thus, there remains a great need for additional safe antigen-
specific immunotherapies, particularly for those with refractory/metastatic solid cancers who have few
therapeutic options. Many cell surface cancer-specific antigens are not proteins but rather complex
carbohydrates that have limited or no expression in normal tissues. For example, β1,6GlcNAc-branched N-
glycans constitute a small subset of the complex-type N-glycans expressed at the surface of normal human cells
but are markedly up-regulated in diverse solid cancers by driver mutations in the receptor tyrosine
kinase/RAS/phosphoinositide-3-kinase(PI3K) signaling pathway. Aberrant over-expression of β1,6GlcNAc-
branched N-glycans in solid tumors drives RTK signaling, tumor growth, motility, invasion, and metastasis. As
both a marker and driver of many diverse cancers, β1,6 GlcNAc-branched N-glycans provide an excellent target
for antigen-specific immunotherapies. However, an antibody to β1,6GlcNAc-branched N-glycans has never been
generated. To address this issue, we generated a novel class of immunotherapeutics that readily target abnormal
glycan antigens with high specificity. We have termed this technology ‘Glycan-dependent T cell Recruiter’
(GlyTR, pronounced ‘glitter’). With funding from the Biden Cancer Moonshot program of the National Cancer
Institute, we developed and optimized the GlyTR1 bi-specific protein that binds both β1,6GlcNAc-branched N-
glycans and CD3 in T cells. The GlyTR1 bi-specific protein induces T cell-dependent killing of a wide diversity of
solid cancers in vitro and in vivo with EC50’s as low as ~50 femtomolar, yet does not kill normal cells or trigger
“on-target, off-cancer” toxicity in humanized mouse models. GlyTR1 is undergoing late-stage IND-enabling
studies and upon FDA approval, the UC Irvine Cancer Center will perform a dose-escalation Phase 1 clinical
trial in relapsed/metastatic solid cancer. However, as GlyTR1 has a short half-life of ~2.5hrs and requires
constant intravenous infusion, herein we propose to develop a longer half-life version of GlyTR1. We also
propose to examine for potential additive/synergistic activity with checkpoint inhibitors. Data from this
proposal will be used to inform future clinical trials following confirmation of safety of GlyTR1 in our Phase 1 trial,
namely whether a longer half-life GlyTR1 and/or co-treatment with checkpoint inhibitors should be pursued.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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MICHAEL DEMETRIOU其他文献
MICHAEL DEMETRIOU的其他文献
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{{ truncateString('MICHAEL DEMETRIOU', 18)}}的其他基金
Regulation of B cell function in demyelinating disease by N-glycan branching
N-聚糖分支调节脱髓鞘疾病中的 B 细胞功能
- 批准号:
10311524 - 财政年份:2019
- 资助金额:
$ 40万 - 项目类别:
Regulation of B cell function in demyelinating disease by N-glycan branching
N-聚糖分支调节脱髓鞘疾病中的 B 细胞功能
- 批准号:
10535482 - 财政年份:2019
- 资助金额:
$ 40万 - 项目类别:
Mechanisms of human immune modulation by oral N-acetylglucosamine
口服N-乙酰氨基葡萄糖调节人体免疫的机制
- 批准号:
9272357 - 财政年份:2014
- 资助金额:
$ 40万 - 项目类别:
Mechanisms of human immune modulation by oral N-acetylglucosamine
口服N-乙酰氨基葡萄糖调节人体免疫的机制
- 批准号:
8851521 - 财政年份:2014
- 资助金额:
$ 40万 - 项目类别:
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