IMAGE GUIDED IMMUNO THERAPY FOR INDUCIBLE ANTIGENS

描述（由申请方提供）：拟定研究的目的是证明放射诱导新抗原可被治疗性抗体靶向的原理。癌症中新抗原的辐射诱导通过癌细胞对DNA链断裂和氧化应激的生理反应发生。这些抗原是在我们的实验室中通过使用噬菌体展示技术和消减免疫发现的，这导致了超过700种单克隆抗体（Platform Technology and Pipeline）。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mAb。基于癌症特异性结合和药代动力学，通过裸鼠中人癌症异种移植物的近红外成像来优先考虑单克隆抗体。先导抗体结合辐射诱导抗原TIP-1、GRP 78和CRT。将首先研究TIP-1的单克隆抗体，因为它在小鼠中的人类癌症中表现出癌症特异性和延长的结合。我们研究了标记抗体的生物分布和药代动力学以及小鼠肿瘤模型。这种针对辐射诱导型TIP-1和GRP 78的mAb被优先考虑，因为裸鼠中16种人癌症中有15种显示出癌症特异性结合。此外，TIP-1和GRP 78仍然与辐射细胞相连，抗体特异性结合癌症数天。在拟定的研究中，将向接受放疗的患者给予放射性标记的抗TIP-1和抗GRP 78抗体。探索性IND指南将使我们能够在接受放射治疗的癌症患者的临床试验中进行概念验证。转诊接受放疗的患者将在入组期间根据疾病类型进行分层。放射治疗后立即静脉内给予Cu 64标记的抗体。患者将在2小时和24小时通过PET扫描成像。如果PET扫描显示每种疾病类型的6名患者中有2名或更多人具有癌症特异性结合，则该抗体将被人源化用于计划的未来I期和II期临床试验。 公共卫生相关性：用放射疗法治疗的预后不良的癌症包括肺癌、胰腺癌、食道癌、乳腺癌、脑癌和直肠癌。这些癌症表现出辐射诱导的肿瘤细胞表面新抗原的表达。我们开发了针对诱导性新抗原的抗体。我们现在将研究这些抗体在接受放射治疗的患者中的药代动力学和生物分布。

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.