Engineered Antibodies as PET Probes for Monitoring Immunotherapy Responses

点击翻译按钮获取中文摘要

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.