Engineered Antibodies as PET Probes for Monitoring Immunotherapy Responses

工程抗体作为 PET 探针监测免疫治疗反应

基本信息

批准号：
10197929
负责人：
Wilson Barry Edwards
金额：
$ 23.48万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10197929
关键词：
Adoptive Transfer Adult Affinity Antibodies Antibody Affinity Biological Biological Markers Biological Monitoring Biomedical Engineering Biomedical Technology Blood Cell Death Cell membrane Cell surface Cell-Mediated Cytolysis Cells Child Cytolysis Cytoplasmic Granules Detection Development Diagnostic Imaging Disease Disease Progression Endocytosis Excision Exhibits Generations Glioma Goals Granzyme Health Human Image Image Enhancement ImmunoPET Immunoglobulin Fragments Immunoglobulin G Immunotherapeutic agent Immunotherapy Label Lymphocyte Lymphocyte Activation Lytic Malignant Glioma Malignant Neoplasms Mediating Mediator of activation protein Mission Modeling Molecular Weight Monitor Mus National Institute of Biomedical Imaging and Bioengineering Outcome Parents Patients Population Positron-Emission Tomography Prediction of Response to Therapy Process Prognosis Public Health Radiation therapy Research Serum Solid Neoplasm Surface Synapses T-Lymphocyte Therapeutic Time Tissues Tracer Translating Translations United States National Institutes of Health antibody engineering cancer immunotherapy cell killing chemotherapy cost cross reactivity cytotoxic cytotoxicity immunosuppressed immunotherapy trials improved ineffective therapies innovation lymphoid neoplasm mouse model neonatal Fc receptor neoplastic cell non-invasive monitor noninvasive diagnosis novel novel strategies patient response perforin personalized medicine pre-clinical prevent residence response serial imaging treatment response tumor uptake

项目摘要

ABSTRACT: Malignant gliomas are deadly tumors in adults and children. Despite tumor resection and radiation therapy (with or without chemotherapy), the prognosis is dismal. Immunotherapy may represent a promising therapeutic strategy for gliomas; however, response rates to immunotherapies have been highly variable. Similar to many other cancers, glioma immunotherapy trials typically continue until disease progression is apparent due to a lack of informative biomarkers. Early monitoring of biologic responses can shorten the duration of ineffective treatments and allow increased opportunities to attempt other therapies but will require accurate assessment of effective biologic responses within the tumor. Novel approaches using immunoPET imaging of lymphocytes to guide immunotherapy include quantification of total lymphocyte populations and lymphocyte activation, although these do not inform on the actual killing of tumor cells. For example, lymphocyte accumulation or activation may not lead to tumor killing when tumors become “invisible” to T-cells, are adoptively transferred, or in highly immunosuppressed tumors. Therefore, development of novel tracers to quantify lymphocyte-mediated tumor cytotoxicity as an early indicator or therapeutic response remains an unmet need. Therefore, we propose to develop immunoPET probes that will unequivocally quantify the extent of cytotoxicity of the T-cells by targeting a cell surface marker CD107a. Our long-term goal is to translation an anti-LGAM engineered antibody for monitoring immunotherapy. The overall objective of this application is to develop novel CD107a-targeted antibody fragments, Mb or Db, for comparison to a mouse Fc-modified anti-CD107a Mab, which can quantify lytic degranulation. Therefore, our central hypothesis is that engineered antibodies will enable quantification of an LGAM and monitoring of immunotherapeutic efficacy. The first aim is to bioengineer a Zr-89-anti-CD107a Mab with species-specific Fc regions for the detection of lytic degranulation of lymphocytes in immunotherapy- treated murine gliomas. The working hypothesis is that reducing serum clearance by increasing antibody affinity for the neonatal Fc receptor will enhance tumor residence time, specific CD107a-mediated uptake, and prediction of immunotherapy responses in gliomas. The second aim is to compare bioengineered Cu-64-labelled minibody and diabody for monitoring lytic degranulation in murine gliomas following immunotherapy. The working hypothesis is that despite faster clearance relative to IgG, the Mbs and Dbs will retain high CD107a-mediated uptake, allow more frequent time points for longitudinal imaging, and enhanced prediction of immunotherapy response in murine gliomas. Upon completion of the research proposed in this application, we expect to have demonstrated that CD107a, a direct biomarker for the cytotoxic action of T-cells, is a viable target for immunoPET for predicting therapeutic response in preclinical murine models of glioma. This contribution is expected to be significant because quantification of CD107a would unequivocally quantify the level of T-cell mediated cytotoxic action for direct correlation to immunotherapy.

摘要：恶性神经胶质瘤是成人和儿童的致命肿瘤。尽管肿瘤切除和辐射治疗（有或不进行化学疗法），预后是令人沮丧的。免疫疗法可能代表一个有前途的神经胶质瘤的治疗策略；但是，对免疫疗法的反应率很高。相似的对于许多其他癌症而言，神经胶质瘤免疫疗法试验通常继续进行，直到疾病进展明显到期缺乏信息性的生物标志物。早期监测生物反应可能会缩短无效的持续时间治疗并允许增加尝试其他疗法的机会，但需要准确评估肿瘤内有效的生物反应。使用淋巴细胞免疫图成像到的新方法指导免疫疗法包括总淋巴细胞群和淋巴细胞激活的数量，尽管这些不会告知实际杀死肿瘤细胞。例如，淋巴细胞的积累或激活可能当肿瘤“不可见” T细胞，适当地转移或高度时，不会导致肿瘤杀死免疫抑制的肿瘤。因此，开发新型示踪剂以量化淋巴细胞介导的肿瘤细胞毒性作为早期指标或治疗反应仍然是未满足的需求。因此，我们建议开发免疫力问题，将通过靶向T细胞的细胞毒性程度明确地量化细胞表面标记CD107A。我们的长期目标是翻译一种抗LGAM工程抗体监测免疫疗法。该应用程序的总体目的是开发新颖的CD107A目标抗体片段，MB或DB，以与小鼠FC修饰的抗CD107A mAb进行比较，该抗CD107A mAb可以量化裂解脱粒。因此，我们的核心假设是工程抗体将实现量化 LGAM和免疫治疗效率的监测。第一个目的是生物工程ZR-89-ANTI-CD107A 具有特异性FC区域的MAB，用于检测免疫疗法中淋巴细胞淋巴细胞的裂解 - 处理的鼠神经胶质瘤。工作假设是通过增加抗体亲和力来降低血清清除率对于新生儿FC受体将增加肿瘤的停留时间，特定的CD107A介导的摄取和胶质瘤中免疫疗法反应的预测。第二个目的是比较生物工程的Cu-64标签免疫疗法后，用于监测鼠神经胶质瘤中裂解脱粒的小型和射击。工作假设是目的地相对于IgG的更快清除率，MB和DBS将保留高CD107A介导吸收，为纵向成像提供更频繁的时间点，并增强了免疫疗法的预测鼠神经胶质瘤的反应。在本申请中提出的研究完成后，我们希望证明CD107A是T细胞细胞毒性作用的直接生物标志物，是免疫集的可行靶标用于预测神经胶质瘤的临床前鼠模型中的治疗反应。预计这项贡献将是显着，因为CD107A的定量将明确量化T细胞介导的细胞毒性水平与免疫疗法直接相关的作用。