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

• 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
• 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

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：恶性胶质瘤是成人和儿童的致命肿瘤。尽管进行了肿瘤切除和放射治疗 治疗（有或没有化疗），预后是惨淡的。免疫疗法可能是一种有前途的 神经胶质瘤的治疗策略;然而，对免疫疗法的反应率是高度可变的。类似 对于许多其他癌症，神经胶质瘤免疫治疗试验通常持续到疾病进展明显， 缺乏有用的生物标志物。早期监测生物学反应可缩短无效的持续时间 治疗并允许增加尝试其他治疗的机会，但需要准确评估 肿瘤内的有效生物反应。使用淋巴细胞的免疫PET成像的新方法， 指导免疫治疗包括总淋巴细胞群和淋巴细胞活化的定量，尽管 这些并不能说明肿瘤细胞的实际杀伤。例如，淋巴细胞积聚或活化可 当肿瘤对T细胞变得"不可见"、过继转移或高度转移时， 免疫抑制肿瘤因此，开发新的示踪剂来定量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PET探针，通过靶向T细胞，明确量化T细胞的细胞毒性程度， 细胞表面标志物CD107a。我们的长期目标是翻译抗LGAM工程抗体， 监测免疫治疗。本申请的总体目标是开发新的CD107 a靶向的抗肿瘤药物。 抗体片段Mb或Db，用于与小鼠Fc修饰的抗CD107a Mab进行比较，其可以定量 溶解性脱粒。因此，我们的中心假设是，工程抗体将能够定量 LGAM和免疫功效监测。第一个目标是生物工程Zr-89-抗CD107a 用于检测免疫治疗中淋巴细胞溶解性脱粒的具有种属特异性Fc区的Mab- 治疗小鼠神经胶质瘤。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，将增加肿瘤停留时间，特异性CD107 a介导的摄取， 神经胶质瘤免疫治疗反应的预测。第二个目的是比较生物工程Cu-64标记的 微抗体和双抗体用于监测免疫治疗后小鼠胶质瘤中的溶解性脱粒。工作 假设尽管相对于IgG清除更快，但Mbs和Db将保留高的CD107 a介导的 摄取，允许更频繁的纵向成像时间点，并增强免疫治疗的预测 小鼠神经胶质瘤的反应。在完成这项申请所建议的研究后，我们预计 证明CD107 a是T细胞细胞毒性作用的直接生物标志物，是免疫PET的可行靶点 用于预测神经胶质瘤临床前鼠模型的治疗反应。预计这笔捐款将 显著，因为CD107a的定量将明确定量T细胞介导的细胞毒性T细胞的水平。 与免疫疗法直接相关的作用。