权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
MICHAEL DEMETRIOU
金额：
$ 40万
依托单位：
GLYTR THERAPEUTICS, INC.
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：
https://reporter.nih.gov/project-details/10766646
关键词：
Address Antibodies Antigen Targeting Antigens B-Cell Neoplasm B-Lymphocytes Binding Binding Proteins Biological Assay Bispecific Antibodies Bite CD3 Antigens CTLA4 gene Cancer Center Cancer Patient Carbohydrates Cell Surface Proteins Cell surface Cells Clinical Trials Combined Modality Therapy Complex Data Detection Development Disease Disease Progression Dose Drug Kinetics FDA approved Fc domain Funding Future Half-Life Human Immune Immune checkpoint inhibitor Immune system Immunoglobulin Fragments Immunosuppressive Agents Immunotherapeutic agent Immunotherapy In Vitro Intravenous infusion procedures Invaded Investigational Therapies Lectin Malignant Neoplasms Metastatic/Recurrent National Cancer Institute National Cancer Program Neoplasm Metastasis Normal Cell Normal tissue morphology Patients Phase Phase I Clinical Trials Phosphatidylinositols Phosphotransferases Polysaccharides Prognosis Proteins Receptor Protein-Tyrosine Kinases Refractory Regulatory T-Lymphocyte Relapse Safety Sequential Treatment Serum Signal Pathway Signal Transduction Solid Solid Neoplasm Specificity Surface Surface Antigens T-Cell Activation T-Cell Receptor T-Lymphocyte Technology Testing Therapeutic Time Toxic effect Transgenic Mice Tumor Antigens Work bi-specific T cell engager cancer cell cancer immunotherapy cell motility cost driver mutation first-in-human humanized mouse immune checkpoint blockade in vitro activity in vivo manufacture mouse model neonatal Fc receptor neonatal human new technology novel novel therapeutics overexpression palliative phase I trial pre-clinical preclinical development prevent programmed cell death protein 1 programs safety assessment stable cell line sugar tumor 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