Improved Tumor Radiotherapy by MORF pretargeting

通过 MORF 预靶向改进肿瘤放射治疗

• 批准号: 6698513
• 负责人: DONALD J HNATOWICH
• 金额: $ 22.66万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6698513
• 关键词: acyltransferase; athymic mouse; autoradiography; disease /disorder model; immunoconjugates; immunoglobulin G; laboratory mouse; neoplasm /cancer; neoplasm /cancer radioimmunotherapy; nonhuman therapy evaluation; pharmacokinetics; radiation therapy dosage; radionuclides; radiotracer; technetium; technology /technique development

Despite several decades of effort, conventional radioimmunotherapy of hematopoietic and especially solid tumors is still providing marginal results. As such, alternative methods of treating these diseases are needed. Arguably one of the most attractive alternative approaches involves pretargeting. Preclinical studies of pretargeting have clearly demonstrated efficacy and early clinical trials are providing encouraging results. These studies usually involve biotin and (strept)avidin. Unfortunately (strept)avidin has been found to be immunogenic and endogenous biotin has been shown to interfere. Another approach, involving bispecific antibodies, replace these difficulties with difficulties in antibody and hapten preparation. Bispecific antibodies also show orders-of-magnitude lower affinities - an important consideration for pretargeting. Investigators at UMMS have been exploring 99mTc-labeled oligonucleotides, one DNA chemical analogue: peptide nucleic acid (PNA) and, most recently, another DNA chemical analogue: morpholinos (MORF) for this application and have shown in preliminary studies that pretargeting with MORFs may potentially solve the above difficulties. We have shown by surface plasmon resonance that the association rate constant of a 18-mer MORF for its MORF complement (cMORF) is equivalent of that of DNAs of comparable lengths and therefor equivalent to that of biotin for (strept)avidin. We have also found that radiolabeled MORFs show rapid clearance kinetics in mice almost exclusively through the kidneys. Furthermore, there is, of course, no endogenous MORF problem. Excellent results have already been obtained with 99mTc-MAG3-MORF administered to LS174T tumor bearing nude mice following the administration of MN-14-cMORF. This study will establish the optimum conditions of dosage and timing for pretargeted localization of 99mTc in tumored mice. These conditions will then be reproduced using MORF labeled with 188Re to investigate the therapeutic potential of this approach, again in tumored mice. This collaborative investigation brings together researchers from Gene Tools and their knowledge of MORF, from Immunomedics and Garden State Cancer Center with their expertise in therapeutic pretargeting and from UMMS who have experience in the radiolabeling and in vivo uses of MORFs and other oligomers. We are confident that these investigations will confirm that pretargeting with MORF can significantly improve upon the therapy now achievable with conventional radioimmunotherapy and may be superior to pretargeting approaches involving biotin/(strept)avidin or bifspecific antibodies.

尽管经过了几十年的努力，造血系统尤其是实体瘤的常规放射免疫疗法仍然只能提供有限的结果。 因此，需要治疗这些疾病的替代方法。 可以说，最有吸引力的替代方法之一就是预先定位。预靶向的临床前研究已清楚地证明了疗效，早期临床试验也提供了令人鼓舞的结果。 这些研究通常涉及生物素和（链霉）亲和素。 不幸的是，（链霉）抗生物素蛋白被发现具有免疫原性，并且内源性生物素已被证明会产生干扰。另一种涉及双特异性抗体的方法用抗体和半抗原制备中的困难来代替这些困难。 双特异性抗体还表现出低几个数量级的亲和力——这是预靶向的一个重要考虑因素。 UMMS 的研究人员一直在探索 99mTc 标记的寡核苷酸、一种 DNA 化学类似物：肽核酸 (PNA) 以及最近的另一种 DNA 化学类似物：吗啉代 (MORF) 的应用，并在初步研究中表明，MORF 的预靶向可能有望解决上述困难。 我们通过表面等离振子共振表明，18 聚体 MORF 与其 MORF 补体 (cMORF) 的关联速率常数与相当长度的 DNA 的关联速率常数相当，因此相当于生物素与（链霉）抗生物素蛋白的关联速率常数。 我们还发现，放射性标记的 MORF 在小鼠中表现出快速的清除动力学，几乎完全通过肾脏。 此外，当然不存在内源性 MORF 问题。 在施用 MN-14-cMORF 后，对荷瘤 LS174T 裸鼠施用 99mTc-MAG3-MORF 已获得优异的结果。 本研究将建立肿瘤小鼠中 99mTc 预靶向定位的最佳剂量和时间条件。 然后使用 188Re 标记的 MORF 重现这些条件，以研究这种方法的治疗潜力，同样是在肿瘤小鼠中。 这项合作研究汇集了来自 Gene Tools 的研究人员及其对 MORF 的了解，来自免疫医学和花园州立癌症中心的研究人员在治疗预靶向方面的专业知识，以及来自 UMMS 的研究人员在 MORF 和其他寡聚物的放射性标记和体内使用方面拥有的经验。 我们相信，这些研究将证实 MORF 预靶向可以显着改善目前常规放射免疫疗法可实现的治疗，并且可能优于涉及生物素/（链霉）亲和素或双特异性抗体的预靶向方法。