RETARGETING AGENTS TO TREAT AML
重新定位药物治疗 AML
基本信息
- 批准号:9267349
- 负责人:
- 金额:$ 38.01万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-05-01 至 2018-04-30
- 项目状态:已结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAffinityAllogenicAntibodiesAntigensApoptosisArchitectureAutologous TransplantationB lymphoid malignancyBispecific AntibodiesBiteBlast CellBone MarrowCD3 AntigensCD34 geneCD47 geneCandidate Disease GeneCell LineCell surfaceCellsClinical TrialsCorrelative StudyCytotoxic T-LymphocytesCytotoxic agentDevelopmentDiagnosticDiseaseDisease remissionDisease-Free SurvivalDoseDose-LimitingDrug KineticsEffector CellFCGR3B geneHematopoieticHematopoietic Stem Cell TransplantationHematopoietic stem cellsHumanIL3RA geneImmuneImmune systemImmunologicsImmunotherapeutic agentImmunotherapyInvestigationIsogenic transplantationMaximum Tolerated DoseMediatingMembrane ProteinsModelingMorbidity - disease rateMusNatural Killer CellsPartial RemissionPatient-Focused OutcomesPatientsPhagocytesPharmacodynamicsPhasePhase I Clinical TrialsPhase II Clinical TrialsPhenotypePopulationPre-Clinical ModelProductionProgressive DiseaseProteinsReagentRecruitment ActivityRefractoryRelapseResearchRestRoleSafetySampling StudiesScheduleSerumStem cellsT-LymphocyteT-Lymphocyte SubsetsTestingTherapeuticTimeToxic effectTranslatingTreatment Failurebasecancer cellchemotherapycomparative efficacycurative treatmentscytokinedesigndifferential expressionefficacy testingexome sequencinghigh riskimmunogenicityimmunoregulationimproved outcomein vivokillingsleukemialeukemic stem cellmacrophagemortalityneoplastic cellnext generationnovelnovel therapeuticsoutcome forecastoverexpressionperipheral bloodpublic health relevanceresponsetumor
项目摘要
DESCRIPTION (provided by applicant): The objective of this research is to develop and translate into early phase clinical trials novel immunotherapeutics for the treatment of Acute Myelogenous Leukemia (AML). Less than half of AML patients are cured with current treatment approaches, and relapse and refractory AML patients who are not candidates for hematopoietic stem cell transplantation (HSCT) have no curative treatment options. The role of the immune system in the control and eradication of leukemia is evident in the reduced relapse rate after allogeneic HSCT compared with syngeneic or autologous transplantation. Since allogeneic HSCT is associated with significant morbidity and mortality, it is important to develop alternative
immunotherapies for AML. We will investigate novel immunotherapeutic approaches for AML in the following specific aims: Aim 1: To conduct a "first-in-human" Phase I clinical trial of MGD006, a CD123×CD3 Dual Affinity Re-Targeting (DART) bi-specific antibody-based molecule, in patients with high risk AML. This study is designed in three segments: a Single Patient Dose Escalation segment, followed by a Multi-Patient Dose Escalation segment and finally a Maximum Tolerated Dose and Schedule expansion segment. Aim 2: We will characterize the immunomodulatory activity and potential anti- tumor activity of MGD006 in patients with AML. Correlative study samples obtained in Aim 1 will be analyzed for (i.) serum cytokines, (ii.) AML and T cell subset numbers, phenotype and function and (iii.) the sub clonal architecture of AML blasts and T cells. Aim 3: We will identify novel targets for immunotherapy in human AML and test the efficacy of new retargeting agents to kill AML blasts expressing CD123 or these novel targets. We will use banked AML and normal CD34+ stem cells to identify differentially expressed surface proteins in AML. We will also examine alternative retargeting agents (CD123xCD16, CD123xCD47, and CD123xCD3xPD1) and effector cells (resting and CIML-NK cells) for their efficacy in killing leukemic blasts. If our phase 1 clinical trial with MGD006 shows a good safety profile with clear and meaningful signs of efficacy in patients deemed to have a poor prognosis, we will pursue further investigation of the approach in a phase 2 trial. Our studies in Aim 3 will attempt to identify novel antigens on AML cells and develop alternative retargeting agents that engage either T cells, NK cells or other immune effector cells.
描述(由申请人提供):本研究的目的是开发用于治疗急性髓性白血病(AML)的新型免疫治疗药物并将其转化为早期临床试验。不到一半的AML患者通过目前的治疗方法治愈,并且不适合造血干细胞移植(HSCT)的复发性和难治性AML患者没有治愈性治疗选择。与同基因或自体移植相比,异基因HSCT后复发率降低,免疫系统在控制和根除白血病中的作用是显而易见的。由于同种异体HSCT与显著的发病率和死亡率相关,因此开发替代疗法非常重要。
AML的免疫疗法。我们将研究AML的新免疫治疗方法,具体目标如下:目标1:在高危AML患者中进行MGD 006(一种基于CD 123 × CD 3双亲和再靶向(DART)双特异性抗体的分子)的“首次人体”I期临床试验。本研究设计为三个部分:单个患者剂量递增部分,随后是多患者剂量递增部分,最后是最大耐受剂量和时间表扩展部分。目的2:我们将表征MGD 006在AML患者中的免疫调节活性和潜在抗肿瘤活性。将分析目标1中获得的相关研究样品的(i.)血清细胞因子,(ii.)AML和T细胞亚群数量、表型和功能,以及(iii.)AML母细胞和T细胞的亚克隆结构。目标三:我们将确定人类AML免疫治疗的新靶点,并测试新的重靶向药物杀死表达CD 123或这些新靶点的AML原始细胞的疗效。我们将使用库存的AML和正常的CD 34+干细胞来鉴定AML中差异表达的表面蛋白。我们还将检查替代重靶向剂(CD 123 xCD 16、CD 123 xCD 47和CD 123 xCD 3xPD 1)和效应细胞(静息和CIML-NK细胞)在杀伤白血病原始细胞方面的疗效。如果我们的MGD 006 I期临床试验显示出良好的安全性特征,在被认为预后不良的患者中具有明确和有意义的疗效体征,我们将在II期试验中进一步研究该方法。我们在Aim 3中的研究将试图鉴定AML细胞上的新抗原,并开发替代的重靶向剂,其参与T细胞、NK细胞或其他免疫效应细胞。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Bispecific Antibodies for the Treatment of Acute Myeloid Leukemia.
- DOI:10.1007/s11899-018-0472-8
- 发表时间:2018-12
- 期刊:
- 影响因子:2.9
- 作者:Guy DG;Uy GL
- 通讯作者:Uy GL
{{
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 }}
John F. Dipersio其他文献
John F. Dipersio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('John F. Dipersio', 18)}}的其他基金
Project 6- Targeting AML using bispecific and antibody drug conjugates
项目 6 - 使用双特异性和抗体药物偶联物靶向 AML
- 批准号:
10615336 - 财政年份:2021
- 资助金额:
$ 38.01万 - 项目类别:
Optimizing Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Malignancies
优化造血干细胞移植治疗血液恶性肿瘤
- 批准号:
10469493 - 财政年份:2017
- 资助金额:
$ 38.01万 - 项目类别:
Pilot Projects and Trans-Network Activities Core
试点项目和跨网络活动核心
- 批准号:
9446709 - 财政年份:2017
- 资助金额:
$ 38.01万 - 项目类别:
Optimizing Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Malignancies
优化造血干细胞移植治疗血液恶性肿瘤
- 批准号:
10001462 - 财政年份:2017
- 资助金额:
$ 38.01万 - 项目类别:
Optimizing Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Malignancies
优化造血干细胞移植治疗血液恶性肿瘤
- 批准号:
10596338 - 财政年份:2017
- 资助金额:
$ 38.01万 - 项目类别:
Optimizing Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Malignancies
优化造血干细胞移植治疗血液恶性肿瘤
- 批准号:
9765193 - 财政年份:2017
- 资助金额:
$ 38.01万 - 项目类别:
Optimizing Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Malignancies
优化造血干细胞移植治疗血液恶性肿瘤
- 批准号:
10738323 - 财政年份:2017
- 资助金额:
$ 38.01万 - 项目类别:
Optimizing Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Malignancies
优化造血干细胞移植治疗血液恶性肿瘤
- 批准号:
10246817 - 财政年份:2017
- 资助金额:
$ 38.01万 - 项目类别:
相似海外基金
Construction of affinity sensors using high-speed oscillation of nanomaterials
利用纳米材料高速振荡构建亲和传感器
- 批准号:
23H01982 - 财政年份:2023
- 资助金额:
$ 38.01万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Affinity evaluation for development of polymer nanocomposites with high thermal conductivity and interfacial molecular design
高导热率聚合物纳米复合材料开发和界面分子设计的亲和力评估
- 批准号:
23KJ0116 - 财政年份:2023
- 资助金额:
$ 38.01万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Platform for the High Throughput Generation and Validation of Affinity Reagents
用于高通量生成和亲和试剂验证的平台
- 批准号:
10598276 - 财政年份:2023
- 资助金额:
$ 38.01万 - 项目类别:
Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants
开发高亲和力和选择性配体作为多巴胺 D4 受体 (D4R) 亚型变体的药理学工具
- 批准号:
10682794 - 财政年份:2023
- 资助金额:
$ 38.01万 - 项目类别:
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233343 - 财政年份:2023
- 资助金额:
$ 38.01万 - 项目类别:
Standard Grant
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233342 - 财政年份:2023
- 资助金额:
$ 38.01万 - 项目类别:
Standard Grant
Molecular mechanisms underlying high-affinity and isotype switched antibody responses
高亲和力和同种型转换抗体反应的分子机制
- 批准号:
479363 - 财政年份:2023
- 资助金额:
$ 38.01万 - 项目类别:
Operating Grants
Deconstructed T cell antigen recognition: Separation of affinity from bond lifetime
解构 T 细胞抗原识别:亲和力与键寿命的分离
- 批准号:
10681989 - 财政年份:2023
- 资助金额:
$ 38.01万 - 项目类别:
CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome
职业:基于亲和力的工程生物材料用于利用干细胞分泌组
- 批准号:
2237240 - 财政年份:2023
- 资助金额:
$ 38.01万 - 项目类别:
Continuing Grant
ADVANCE Partnership: Leveraging Intersectionality and Engineering Affinity groups in Industrial Engineering and Operations Research (LINEAGE)
ADVANCE 合作伙伴关系:利用工业工程和运筹学 (LINEAGE) 领域的交叉性和工程亲和力团体
- 批准号:
2305592 - 财政年份:2023
- 资助金额:
$ 38.01万 - 项目类别:
Continuing Grant