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

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)
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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

Cancer Immunotherapy Targeting Tn Antigen
针对 Tn 抗原的癌症免疫疗法
  • 批准号:
    10326021
  • 财政年份:
    2021
  • 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:
    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:
N-glycosylation and Immunotherapy for cancer
N-糖基化和癌症免疫治疗
  • 批准号:
    10465041
  • 财政年份:
    2018
  • 资助金额:
    $ 40万
  • 项目类别:
N-glycosylation and Immunotherapy for cancer
N-糖基化和癌症免疫治疗
  • 批准号:
    10229448
  • 财政年份:
    2018
  • 资助金额:
    $ 40万
  • 项目类别:
O-Glycan-dependent Immunotherapy for Cancer
O-聚糖依赖性癌症免疫疗法
  • 批准号:
    9988594
  • 财政年份:
    2018
  • 资助金额:
    $ 40万
  • 项目类别:
N-glycosylation and Immunotherapy for cancer
N-糖基化和癌症免疫治疗
  • 批准号:
    9789858
  • 财政年份:
    2018
  • 资助金额:
    $ 40万
  • 项目类别:
N-glycosylation and Immunotherapy for cancer
N-糖基化和癌症免疫治疗
  • 批准号:
    10005189
  • 财政年份:
    2018
  • 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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