IMAGE GUIDED IMMUNO THERAPY FOR INDUCIBLE ANTIGENS

描述（由申请人提供）：拟议研究的目的是证明放射诱导的新抗原可以与治疗性抗体靶向的原理。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发生的。这些抗原是在我们的实验室通过使用噬菌体显示技术和减法免疫发现的，已经产生了700多种单克隆抗体（平台技术和管道）。该平台技术已经发现了几种针对不同辐射诱导蛋白的先导单抗。基于癌症特异性结合和药代动力学，单克隆抗体在裸鼠中被人类癌症异种移植物近红外成像优先考虑。导联抗体结合辐射诱导抗原TIP-1、GRP78和CRT。针对TIP-1的单克隆抗体将首先被研究，因为它在人类癌症小鼠中显示出癌症特异性和长时间的结合。我们研究了标记抗体和小鼠肿瘤模型的生物分布和药代动力学。该单抗针对辐射诱导的TIP-1和GRP78被优先考虑，因为16种人类癌症中有15种在裸鼠中表现出癌症特异性结合。此外，TIP-1和GRP78在照射后的细胞上停留数天，抗体特异性地与癌细胞结合。在拟议的研究中，放射性标记的抗tip -1和抗grp78抗体将给予接受放疗的患者。探索性IND指南将允许我们在接受放射治疗的癌症患者的临床试验中进行概念验证。转诊放疗的患者应根据疾病类型进行分层治疗。放疗后立即静脉注射Cu64标记抗体。患者将在2小时和24小时进行PET扫描。如果PET扫描显示每种疾病类型的6名患者中有2名或更多的患者具有癌症特异性结合，那么该抗体将被人源化，用于计划中的未来I期和II期临床试验。

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.