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.

尽管努力了数十年，但造血，尤其是实体瘤的常规放射免疫疗法仍在提供边际结果。 因此，需要替代治疗这些疾病的方法。 可以说，最有吸引力的替代方法之一是预先制定的。预先试验的临床前研究清楚地证明了功效，早期临床试验正在提供令人鼓舞的结果。 这些研究通常涉及生物素和（链球菌）抗生物素。 不幸的是（链球菌）抗生蛋白蛋白是免疫原性的，并且已证明内源性生物素会干扰。涉及双特异性抗体的另一种方法，用抗体和触觉制剂中的困难取代了这些困难。 双特异性抗体还显示了降低级别的亲和力 - 有限的重要考虑因素。 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），最近，在此应用中，用于使用MORFS的初步研究中显示了一种潜在的解决方案。 我们已经通过表面等离子体共振表明，其MORF补体（CMORF）的缔合速率常数等同于可比长度的DNA，因此与生物素相当于（链球菌）的抗生物素。 我们还发现，放射性标记的MORF几乎完全通过肾脏显示了小鼠的快速清除动力学。 此外，当然，没有内源性的MORF问题。 在使用Mn-14-Cmorf后，已经用99mtc-MAG3-MORF给予LS174T肿瘤裸鼠的99mtc-MAG3-MORF获得了出色的结果。 这项研究将确定在肿瘤小鼠中剂量的99mtc定位的最佳剂量和时机条件。 然后，将使用带有188RE标记的MORF再现这些条件，以研究这种方法的治疗潜力，再次在肿瘤的小鼠中。 这项合作调查将基因工具的研究人员及其对MORF的了解，从免疫医学和花园州癌症中心及其在治疗有限的预定性方面的专业知识，以及在放射性映射和体内使用Morfs和其他低聚物方面经验丰富的UMMS。 我们有信心这些研究将确认使用MORF进行预先进行的预期可以在传统的放射免疫疗法中可以显着改善这种疗法，并且可能优于涉及生物素/（链球菌）Avidin或Bifspepspecipic抗体的预先定位方法。