IMAGE GUIDED IMMUNO THERAPY FOR INDUCIBLE ANTIGENS

诱导抗原的图像引导免疫治疗

基本信息

批准号：
8374016
负责人：
DENNIS E HALLAHAN
金额：
$ 20万
依托单位：
WASHINGTON 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：
2012-09-26 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8374016
关键词：
Anaplasia Animals Antibodies Antigens Binding Biodistribution Brain Breast Cancer Patient Cancer Prognosis Cell membrane Cell surface Cells Clinical Clinical Research Clinical Trials DNA strand break Development Disease Drug Delivery Systems Drug Kinetics E-Selectin ERBB2 gene Endoplasmic Reticulum Esophagus Future Genomics Glioblastoma Goals Guidelines Head and neck structure Hour Human Image Immunization Immunoglobulin G Immunohistochemistry Intercellular adhesion molecule 1 Ionizing radiation Label Laboratories Lead Ligand Binding Location Low Dose Radiation Malignant Glioma Malignant Neoplasms Malignant neoplasm of lung Mediating Membrane Proteins Molecular Target Monoclonal Antibodies Mus Normal tissue morphology Nude Mice Oxidative Stress P-Selectin Pancreas Patients Peptide Phage Display Library Phage Display Phagocytosis Phase Physiological Positron-Emission Tomography Protein translocation Proteins Proteomics Radiation Radiation therapy Radioimmunoconjugate Radiolabeled Rectum Research Staining method Stains Surface Taxes Technology Testing Therapeutic antibodies Vascular Cell Adhesion Molecule-1 Xenograft procedure antibody-dependent cell cytotoxicity base calreticulin cancer cell drug development glucose-regulated proteins improved irradiation mouse model neoplastic cell overexpression prognostic radiotracer response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The goal of the proposed research is to prove the principle that radiation inducible neoantigens can be targeted with therapeutic antibodies. Radiation induction of neoantigens in cancer occurs through the physiologic response of cancer cells to DNA strand breaks and oxidative stress. These antigens are discovered in our laboratory through the use of phage displayed technology and subtractive immunization which has led to over 700 monoclonal antibodies (Platform Technology and Pipeline). This platform technology has discovered several lead mAb's to distinct radiation inducible proteins. Monoclonal antibodies are prioritized by near infrared imaging of human cancer xenografts in nude mice based upon cancer specific binding and pharmacokinetics. The lead antibodies bind to radiation inducible antigens TIP-1, GRP78 and CRT. The monoclonal antibody to TIP-1 will be studied first because it demonstrates cancer specific and prolonged binding in human cancers in mice. We studied the biodistribution and pharmacokinetics of labeled antibody and mouse models of cancer. This mAb to radiation inducible TIP-1 and GRP78 are prioritized because 15 of 16 human cancers in nude mice show cancer specific binding. Moreover, TIP-1 and GRP78 remain tethered to the irradiated cell and antibodies bind specifically to the cancer for several days. In the proposed study, radiolabeled anti-TIP-1 and anti-GRP78 antibodies will be administered to patients receiving radiotherapy. The exploratory IND guidelines will allow us to conduct proof of concept in clinical trials in cancer patients receiving radiotherapy for these incurable cancers. Patients who are referred for radiotherapy will be stratified during accrual according to disease type. Cu64 - labeled antibody will be administered intravenously immediately after radiotherapy. Patients will be imaged by PET scans at 2, and 24 hours. If PET scans show cancer specific binding in 2 or more out of 6 patients in each disease type, then the antibody will be humanized for planned future Phase I and II clinical trials. PUBLIC HEALTH RELEVANCE: Poor prognostic cancers that are treated with radiation therapy include cancers of the lung, pancreas, esophagus, breast, brain and rectum. These cancers show radiation-induced expression of new antigens on the surface of neoplastic cells. We developed antibodies to the inducible neoantigens. We will now study the pharmacokinetics and biodistribution of these antibodies in patients receiving radiotherapy.

描述（由申请人提供）：拟议的研究的目的是证明可以用治疗抗体靶向辐射诱导的新抗原的原则。癌症中新抗原的辐射诱导是通过癌细胞对DNA链断裂和氧化应激的生理反应而发生的。这些抗原是通过使用噬菌体展示的技术和减法免疫的，在我们的实验室中发现了这些抗原，这导致了700多个单克隆抗体（平台技术和管道）。该平台技术已经发现了几个铅mab的辐射诱导蛋白。通过基于癌症特异性结合和药代动力学对裸鼠的人类癌症异种移植物的近红外成像，将单克隆抗体优先考虑。铅抗体与辐射诱导抗原TIP-1，GRP78和CRT结合。首先研究对TIP-1的单克隆抗体，因为它在小鼠的人类癌症中表现出癌症特异性和长时间结合。我们研究了标记的抗体和癌症小鼠模型的生物分布和药代动力学。该对辐射诱导的TIP-1和GRP78的MAB优先考虑，因为裸鼠的16个人癌中有15个显示出癌症特异性结合。此外，TIP-1和GRP78仍然束缚在辐照细胞上，抗体与癌症特异性结合了几天。在拟议的研究中，将对接受放射疗法的患者进行放射标记的抗TIP-1和抗GRP78抗体。探索性IND指南将使我们能够在接受这些无法治愈的癌症的癌症患者的临床试验中进行概念证明。根据疾病类型，应在应计时对被转诊进行放疗的患者进行分层。 Cu64-标记的抗体将在放疗后立即静脉内给药。患者将在2和24小时时通过PET扫描对患者进行成像。如果PET扫描在每种疾病类型的6例患者中有2例中有2个或更多的癌症特异性结合，则该抗体将用于计划的未来I和II期临床试验。公共卫生相关性：接受放射疗法治疗的预后癌不良包括肺癌，胰腺，食道，乳房，脑和直肠。这些癌症在肿瘤细胞表面显示出辐射诱导的新抗原的表达。我们开发了对诱导型新抗原的抗体。现在，我们将研究接受放疗的患者中这些抗体的药代动力学和生物分布。