IMAGE GUIDED IMMUNO THERAPY FOR INDUCIBLE ANTIGENS

描述（由申请人提供）：拟议研究的目标是证明放射诱导新抗原可以用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而发生的。这些抗原是我们实验室通过使用噬菌体展示技术和消减免疫发现的，从而产生了 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克隆抗体。基于癌症特异性结合和药代动力学，通过对裸鼠中的人类癌症异种移植物进行近红外成像来优先考虑单克隆抗体。先导抗体与辐射诱导抗原 TIP-1、GRP78 和 CRT 结合。将首先研究 TIP-1 的单克隆抗体，因为它在小鼠体内展示了癌症特异性和与人类癌症的长期结合。我们研究了标记抗体和小鼠癌症模型的生物分布和药代动力学。这种针对辐射诱导型 TIP-1 和 GRP78 的 mAb 受到优先考虑，因为裸鼠体内 16 种人类癌症中有 15 种显示出癌症特异性结合。此外，TIP-1 和 GRP78 仍与受辐射的细胞结合，并且抗体与癌症特异性结合数天。在拟议的研究中，放射性标记的抗 TIP-1 和抗 GRP78 抗体将给予接受放射治疗的患者。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。转诊接受放射治疗的患者将在累积期间根据疾病类型进行分层。 Cu64 标记的抗体将在放射治疗后立即静脉注射。患者将在 2 小时和 24 小时进行 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，用于计划的未来 I 期和 II 期临床试验。 公众健康相关性：采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。这些癌症在肿瘤细胞表面显示辐射诱导的新抗原表达。我们开发了针对可诱导新抗原的抗体。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.