Novel Immunotherapies for Lymphoid Malignancies

淋巴恶性肿瘤的新型免疫疗法

基本信息

批准号：
8658041
负责人：
JOHN C. BYRD
金额：
$ 30.69万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-20 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8658041
关键词：
1-Phosphatidylinositol 3-Kinase Acute Lymphocytic Leukemia Alternative Therapies Antibodies Antigens Apoptosis Apoptotic B lymphoid malignancy B-Lymphocytes BCL2L11 gene Binding C-terminal CD37 antigen CDW52 gene Cell Death Cell Nucleus Cell Survival Cells Cessation of life Chronic Lymphocytic Leukemia Clinical Clinical Trials Data Development Disease Effectiveness Effector Cell FOXO3A gene Generations Genes Goals Immune Immunologic Receptors Immunology Immunotherapy In Vitro Intervention Knowledge Lead Ligation Lymphoma MS4A1 gene Malignant Neoplasms Malignant lymphoid neoplasm Mature B-Lymphocyte Mediating Modification N-terminal NR0B2 gene Natural Killer Cells Non-Hodgkin&apos s Lymphoma Outcome Patients Peptides Phagocytosis Pharmacologic Substance Pharmacy (field)Phase Phase I Clinical Trials Phosphorylation Pre-Clinical Model Progression-Free Survivals Proteins Proto-Oncogene Proteins c-akt Reagent Relapse Research Role Signal Transduction Small Interfering RNA Structure Therapeutic Therapeutic antibodies Toxic effect Treatment Efficacy Tumor Suppressor Proteins Tyrosine Work adult leukemia alemtuzumab base cell killing chemotherapy chimeric antibody cytotoxic cytotoxicity human PHEMX protein improved in vivo killings kinase inhibitor leukemia man monocyte neoplastic cell novel pre-clinical preclinical study programs response rituximab selective expression success therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia and remains incurable. The introduction of the CD20 antibody rituximab combined with chemotherapy (chemoimmunotherapy) was the first intervention that has been shown to impact survival of CLL patients. Building upon the success of antibody directed therapy in CLL, we have actively pursued development of similar therapies directed at alternative antigens expressed selectively on CLL cells. CD37 is a tetraspanin protein of uncertain function that is expressed predominately on mature B-cells. Our research group has worked with Trubion Pharmaceutics, Inc/Emergent Biosolutions to develop CD37 directed TRU-016, a small modular immune pharmaceutical similar to an antibody but lacking the CH1 domain. Prior pre-clinical work demonstrated TRU-016 to have potent direct and immune based killing of CLL cells and also in vivo activity in several lymphoma pre-clinical models. A first in man phase 1 clinical trial initiated with TRU-016 in previously treated CLL has demonstrated single agent activity and combination studies have now been initiated. During this early phase 1 development of TRU-016 we have continued pre-clinical work to discern its mechanism of action. Preliminary data described in this proposal demonstrate that TRU-016 ligation of the CD37 antigen causes recruitment and phosphorylation of SHP1 via a potential ITIM domain within the intracytplasmic domain. SHP1 activation leads to decreased PI3-Kinase activity and AKT phosphorylation concomitant with FOXO3A accumulation in the nucleus and induction of the pro-apoptotic gene BIM and CLL cell death. siRNA targeting either SHP1 or BIM antagonizes death induced by TRU-016. Interestingly, the C-terminal of the CD37 protein contains ITAM like motif with associated activation function. Deletion of this motif enhances TRU-016 induced cytotoxicity suggesting a potential negative regulatory role for the C-terminal in TRU-016 cytotoxic effect. Consistent with this, inhibition of pro-survival signaling by PI3K and BTK overcame the inhibitory effects of the C-terminal domain resulting in enhanced TRU-016 induced apoptosis. Moving forward, this proposal seeks to further characterize in detail the ITIM and ITAM function of CD37 activated by TRU-016, study the mechanisms of cross talk between the activation and inhibitory signaling relevant to TRU-016 response and pursue development of afucosylated TRU-016 (TRU-016GV) leading to rational combination strategies that will facilitate enhanced TRU-016 and TRU-016GV response. Knowledge gained from this proposal has potential to impact not only CLL but also lymphoma and acute lymphoblastic leukemia patients who may also derive benefit from TRU-016 or TRU-016GV. Additionally, mechanistic study of CD37 ITIM and ITAM dual signaling has relevance to general B-cell immunology. The senior investigative team formed to perform this project includes expertise to accomplish the proposed goals and support from a large internationally known leukemia program. Collectively, TRU-016 and its application to CLL therapy have potential to transform treatment of this disease.

描述（由申请人提供）：慢性淋巴细胞白血病（CLL）是成人白血病最常见的类型，并且仍然无法治愈。 CD20 抗体利妥昔单抗联合化疗（化学免疫疗法）的引入是第一个被证明可以影响 CLL 患者生存的干预措施。在 CLL 抗体导向疗法取得成功的基础上，我们积极致力于开发针对 CLL 细胞选择性表达的替代抗原的类似疗法。 CD37 是一种功能不确定的四跨膜蛋白，主要在成熟 B 细胞上表达。我们的研究小组与 Trubion Pharmaceutics, Inc/Emergent Biosolutions 合作开发了 CD37 导向的 TRU-016，这是一种类似于抗体但缺乏 CH1 结构域的小型模块化免疫药物。先前的临床前工作证明 TRU-016 对 CLL 细胞具有有效的直接和基于免疫的杀伤作用，并且在几种淋巴瘤临床前模型中也具有体内活性。在先前治疗过的 CLL 中使用 TRU-016 启动的首次人体 1 期临床试验已证明单药活性，联合研究现已启动。在 TRU-016 的早期第一阶段开发过程中，我们继续进行临床前工作，以了解其作用机制。该提案中描述的初步数据表明，CD37 抗原的 TRU-016 连接导致 SHP1 通过胞质内结构域内的潜在 ITIM 结构域进行募集和磷酸化。 SHP1 激活导致 PI3 激酶活性和 AKT 磷酸化降低，同时 FOXO3A 在细胞核中积累，并诱导促凋亡基因 BIM 和 CLL 细胞死亡。靶向 SHP1 或 BIM 的 siRNA 可拮抗 TRU-016 诱导的死亡。有趣的是，CD37 蛋白的 C 末端包含具有相关激活功能的 ITAM 样基序。该基序的缺失增强了 TRU-016 诱导的细胞毒性，表明 C 端在 TRU-016 细胞毒性作用中具有潜在的负调节作用。与此相一致的是，PI3K 和 PI3K 抑制促生存信号传导 BTK 克服了 C 末端结构域的抑制作用，导致 TRU-016 诱导的细胞凋亡增强。展望未来，该提案旨在进一步详细描述 TRU-016 激活的 CD37 的 ITIM 和 ITAM 功能，研究与 TRU-016 响应相关的激活和抑制信号之间的串扰机制，并开发无岩藻糖基化的 TRU-016 （TRU-016GV）导致合理的组合策略，这将有助于增强 TRU-016 和 TRU-016GV 的反应。从该提案中获得的知识不仅有可能影响 CLL，还可能影响淋巴瘤和急性淋巴细胞白血病患者，他们也可能从 TRU-016 或 TRU-016GV 中受益。此外，CD37 ITIM 和 ITAM 双重信号传导的机制研究与一般 B 细胞免疫学相关。为执行该项目而组建的高级调查团队包括实现拟议目标的专业知识以及来自大型国际知名白血病项目的支持。总的来说，TRU-016 及其在 CLL 治疗中的应用有潜力改变这种疾病的治疗。