IMAGE GUIDED IMMUNO THERAPY FOR INDUCIBLE ANTIGENS

描述(申请人提供)：拟议研究的目标是证明放射诱导的新抗原可以被治疗性抗体靶向的原理。肿瘤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噬菌体展示技术和消减免疫技术发现的，已经产生了700多种单抗(Platform Technology和Pipeline)。这一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。基于肿瘤特异性结合和药代动力学，人癌裸鼠移植瘤的近红外成像优先考虑单抗。铅抗体与辐射诱导抗原TIP-1、GRP78和CRT结合。首先将研究抗TIP-1的单抗，因为它在小鼠体内显示出癌症特异性和对人类癌症的长期结合。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。这种抗辐射诱导的TIP-1和GRP78的mAb之所以被优先考虑，是因为在裸鼠体内的16种人类癌症中，有15种表现出癌症特异性结合。此外，TIP-1和GRP78仍然与受辐射的细胞捆绑在一起，抗体与癌症特异性结合几天。在这项拟议的研究中，放射性标记的抗TIP-1和抗GRP78抗体将用于接受放射治疗的患者。探索性的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。转介接受放射治疗的患者将根据疾病类型在累计期内进行分层。Cu64标记抗体将在放疗后立即静脉注射。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名或更多人与癌症特异性结合，那么抗体将被人源化，用于计划中的未来I期和II期临床试验。 公共卫生相关性：接受放射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。这些癌症表现为辐射诱导的肿瘤细胞表面新抗原的表达。我们研制出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.