Cancer Immunotherapy Targeting Tn Antigen
针对 Tn 抗原的癌症免疫疗法
基本信息
- 批准号:10326021
- 负责人:
- 金额:$ 39.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAntibodiesAntigensB lymphoid malignancyBindingBinding ProteinsBiteBlood group antigen SCD3 AntigensCarbohydratesCell LineCell Surface ProteinsCell surfaceCellsClinicalComplexContinuous Intravenous InfusionDevelopmentEngineeringFDA approvedGalactoseGenerationsGrowthHalf-LifeHematologic NeoplasmsHematopoietic NeoplasmsHospitalsHumanHuman ActivitiesImmuneImmune systemImmunotherapeutic agentImmunotherapyIn VitroIn complete remissionIndividualLectinLinkLiquid substanceLiverLocationLymphocyteMalignant NeoplasmsMediatingMonoclonal AntibodiesMusNormal tissue morphologyParentsPolysaccharidesProtein EngineeringProteinsPumpRecyclingRiskSafetySensitivity and SpecificitySerumSerum AlbuminSolidT-LymphocyteTechnologyTherapeuticTimeTn antigenToxic effectTreatment ProtocolsTumor AntigensTumor-Associated Carbohydrate AntigensXenograft procedurebasebi-specific T cell engagercancer cellcancer immunotherapeuticscancer immunotherapycancer typechimeric antigen receptor T cellsclinical candidatecostdrug developmentexperimental studyglycosylationimprovedin vitro activityin vivomacrophagemeetingsneonatal Fc receptornew technologynonhuman primatenovelpharmacokinetics and pharmacodynamicspreclinical developmentstem cellssugartherapeutic proteintreatment duration
项目摘要
Abstract
Cancer immunotherapeutic bi-specific proteins and engineered Chimeric Antigen Receptor T cells (CAR
T) have shown remarkable clinical activity, with complete response rates as high as ~90% for B cell malignancies.
However, applying these two therapeutic approaches to the vast majority of cancer types is restricted
by multiple factors. First, there are only a small number of known cell-surface proteins that are sufficiently
specific to cancer to safely allow targeting by antibodies. This is particularly true for solid cancers, where unlike
hematopoietic malignancies; loss of healthy cells cannot be readily replenished by stem cell progenitors. Second,
as each individual bi-specific protein and/or CAR T cell only target a single cancer type, different bi-specific
and/or CAR T cells will need to be developed for each cancer type. This greatly increases development time and
costs. Third, neither therapy is able to effectively target the most abundant and widely expressed cell surface
cancer antigens known, namely Tumor associated carbohydrate antigens (TACA’s). Many cancer specific
antigens are not proteins, but rather complex carbohydrates that have limited or no expression in normal tissues.
Indeed, altered glycosylation is a near universal feature of cancer. While TACA’s have been known for decades,
generation of effective monoclonal antibodies specific to complex carbohydrates has proven to be very
challenging, greatly limiting their usefulness as targets for cancer immunotherapy. Here we propose to address
these issues and develop a novel class of immunotherapeutics that target the Tn antigen, an abnormal
O-linked carbohydrate common on many solid and hematopoietic cancers but not present on normal
tissue. We have termed this technology as Glycan-dependent T cell Recruiter (GlyTR, pronounced
‘glitter’). We have generated and optimized a GlyTR bi-specific protein that 1) specifically binds to both Tn
antigen and CD3, 2) activated T cells in the presence but not absence of Tn+ cancer cells and 3) induced T cell
dependent killing of diverse solid and liquid cancer cells in vitro and in vivo. However, serum half-life was ~2 hrs,
which is similar to the FDA approved bi-specific protein Blincyto that requires continuous intravenous infusion
(via a pump) over 28-days (first 9 days in hospital). To avoid this cumbersome treatment regimen for GlyTR,
here we propose to extend the half-life by adding a human-serum albumin (HSA) domain. The half-life of HSA
is ~3 weeks and has been successfully fused to therapeutic proteins to markedly increase half-life, including two
FDA approved therapeutics. Here we propose to genetically fuse HSA to GlyTR (HSA-GlyTR) and confirm
binding to Tn antigen, cancer-killing activity and improved half-life. Specifically, we propose the following two
Aims. Aim 1 optimizes the HSA-GlyTR bi-specific protein for activity and drug development. Aim 2 explores the
efficacy and safety of the optimized HSA-GlyTR bi-specific protein. If successful, these experiments will allow
subsequent IND enabling studies to develop an entire new class of cancer killing immunotherapeutic’s uniquely
capable of targeting multiple solid and hematopoietic cancers with a single therapeutic.
摘要
肿瘤免疫治疗双特异性蛋白与工程化嵌合抗原受体T细胞
T)表现出显著的临床活动性,对B细胞恶性肿瘤的完全缓解率高达90%。
然而,将这两种治疗方法应用于绝大多数癌症类型是有限的。
受到多种因素的影响。首先,只有一小部分已知的细胞表面蛋白足以
对癌症的特异性,以安全地允许通过抗体靶向。对于实体癌尤其如此,不同于
恶性血液病;健康细胞的丧失不能很容易地由干细胞前体来补充。第二,
因为每个单独的双特异性蛋白和/或CAR T细胞只针对一种癌症类型、不同的双特异性
和/或CAR T细胞将需要针对每种癌症类型进行培养。这极大地增加了开发时间和
成本。第三,两种疗法都不能有效地针对最丰富和最广泛表达的细胞表面
已知的肿瘤抗原,即肿瘤相关糖类抗原(TACA‘s)。许多癌症特异性的
抗原不是蛋白质,而是在正常组织中有限表达或不表达的复杂碳水化合物。
事实上,糖基化改变几乎是癌症的普遍特征。虽然TACA已经被知道了几十年,
针对复杂碳水化合物的有效单抗的产生已被证明是非常
具有挑战性,极大地限制了它们作为癌症免疫治疗靶点的有效性。在这里,我们建议解决
这些问题并开发了一类针对TN抗原的新型免疫疗法,TN抗原是一种异常的
O-连接碳水化合物常见于许多实体和造血系肿瘤,但在正常人群中不存在
组织。我们将这项技术称为糖依赖T细胞招募器(Glytr,发音为
《闪闪发光》)。我们已经产生并优化了一种GlyTR双特异性蛋白,它可以1)与两种TN特异性结合
抗原和CD3,2)在TN+癌细胞存在而不是不存在的情况下激活T细胞,以及3)诱导T细胞
体外和体内对多种固体和液体癌细胞的依赖杀伤作用。而血清半衰期为~2小时,
这类似于FDA批准的需要持续静脉输注的双特异性蛋白质Blincyto
(通过泵)超过28天(前9天住院)。为了避免GlyTR的这种繁琐的治疗方案,
在这里,我们建议通过增加人血清白蛋白(HSA)结构域来延长半衰期。人血清白蛋白的半衰期
是~3周,并已成功地与治疗性蛋白融合,显著延长半衰期,包括两个
FDA批准的治疗方法。在这里,我们建议将HSA基因融合到Glytr(HSA-Glytr),并确认
结合TN抗原,杀癌活性和改善半衰期。具体地说,我们提出了以下两点
目标。目的1优化人血清白蛋白-甘氨酸受体双特异性蛋白的活性和药物开发。《目标2》探索
优化的人血清白蛋白-甘氨酸双特异性蛋白的有效性和安全性。如果成功,这些实验将允许
随后的IND使研究能够开发出一种全新的抗癌免疫疗法
能够通过一次治疗针对多个实体和造血系癌症。
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)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
MICHAEL DEMETRIOU其他文献
MICHAEL DEMETRIOU的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('MICHAEL DEMETRIOU', 18)}}的其他基金
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
- 批准号:
10766646 - 财政年份:2023
- 资助金额:
$ 39.82万 - 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:
$ 39.82万 - 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:
$ 39.82万 - 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:
$ 39.82万 - 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:
$ 39.82万 - 项目类别:
相似海外基金
Rationally guided discovery platform for monoclonal antibodies against carbohydrate antigens using virus-like particle conjugate immunization and high throughput selection
使用病毒样颗粒缀合物免疫和高通量选择的合理引导的针对碳水化合物抗原的单克隆抗体的发现平台
- 批准号:
10574738 - 财政年份:2023
- 资助金额:
$ 39.82万 - 项目类别:
Assessing the role of liver stage antigens-specific antibodies against Plasmodium falciparum liver stage infection
评估肝期抗原特异性抗体对抗恶性疟原虫肝期感染的作用
- 批准号:
10392870 - 财政年份:2021
- 资助金额:
$ 39.82万 - 项目类别:
Generation of antibodies specific for optimal non-HRP2 malaria diagnostic antigens
生成最佳非 HRP2 疟疾诊断抗原的特异性抗体
- 批准号:
10092930 - 财政年份:2020
- 资助金额:
$ 39.82万 - 项目类别:
Generation of antibodies specific for optimal non-HRP2 malaria diagnostic antigens
生成最佳非 HRP2 疟疾诊断抗原的特异性抗体
- 批准号:
9896170 - 财政年份:2020
- 资助金额:
$ 39.82万 - 项目类别:
Interrogation of cell surface antigens on B lineage cells using structurally unique variable lymphocyte receptor antibodies of the evolutionarily distant sea lamprey
使用进化遥远的海七鳃鳗结构独特的可变淋巴细胞受体抗体询问 B 谱系细胞上的细胞表面抗原
- 批准号:
433456 - 财政年份:2020
- 资助金额:
$ 39.82万 - 项目类别:
Operating Grants
Investigations of interactions between various natural antibodies and food-derived antigens
研究各种天然抗体与食物源性抗原之间的相互作用
- 批准号:
19K15765 - 财政年份:2019
- 资助金额:
$ 39.82万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Identifying Kawasaki Disease-Specific Antibodies and Antigens
识别川崎病特异性抗体和抗原
- 批准号:
9932769 - 财政年份:2018
- 资助金额:
$ 39.82万 - 项目类别:
Novel Scoring Methods for Interactions between Antibodies and Antigens
抗体和抗原之间相互作用的新评分方法
- 批准号:
BB/P504713/1 - 财政年份:2017
- 资助金额:
$ 39.82万 - 项目类别:
Training Grant
Novel Scoring Methods for Interactions between Antibodies and Antigens
抗体和抗原之间相互作用的新评分方法
- 批准号:
1932904 - 财政年份:2017
- 资助金额:
$ 39.82万 - 项目类别:
Studentship
SBIR Phase II: Automated Design Methods of Antibodies Directed to Protein and Carbohydrate Antigens
SBIR II 期:针对蛋白质和碳水化合物抗原的抗体的自动化设计方法
- 批准号:
1632399 - 财政年份:2016
- 资助金额:
$ 39.82万 - 项目类别:
Standard Grant