Metal Chelate Conjugated Monoclonal Antibodies for Tumor Diagnosis and Therapy

肿瘤相关单克隆抗体（mAbs）作为细胞毒性药物对恶性细胞的选择性载体是一种治疗药物。这一假设在动物模型系统中进行了测试，其中单克隆抗体针对与各种恶性肿瘤相关的抗原。使用的细胞杀伤剂是粒子发射放射性核素，并在适当的小鼠肿瘤异种移植模型系统中评估了它们的相对功效。选择用于研究的放射性核素跨越了可用的放射性核素性质的范围，从而允许测定发射能量、半衰期和发射类型的影响。目前的研究继续集中在对α粒子发射放射性核素212Pb、213Bi和211At进行广泛的临床前研究。正在进行的协同临床试验使用第二代双功能螯合剂1b4 -DTPA（又名MX-DTPA或tixetan）来隔离90Y，然而，几乎所有的协同临床试验现在都使用第三代双功能螯合剂CHX-A“DTPA”来隔离111In、90Y、213Bi，现在可能还有177Lu。今年开始的研究继续验证CHX-A“DTPA”用于86Y正电子发射断层扫描（PET）成像的使用，而同样建立的213Bi螯合化学继续用于临床前和临床研究。新型双功能螯合剂和靶向放射治疗的连接剂的临床前评估主要是关于偶联化学选择的改进和放射性标记的改进。这些改进源于扩展的组合，以提供肽化学剂以及位点特异性偶联策略，可用于放射性镧系元素和α粒子发射放射性核素（如213Bi）。与这些改进同时，一种具有活性酯部分的新型双功能交叉桥cyclam被开发出来，用于Cu-64，应该证明对PET成像和治疗都有用。此外，现有双功能螯合剂的新型连接化学已经开发出来，也适用于肽的使用，甚至在肽合成器仪器中使用。因此，化学部分的许多已建立的试剂现在正在扩展到肽和其他针对感兴趣的受体（如粘附体）的小传递载体。在最稳定的2111at连接试剂N-Me-SAPS验证后暂时中断的2111at研究将在今年晚些时候恢复，以开展与其他α发射器治疗弥散性腹腔内疾病的平行研究。使用212Bi和212Pb治疗弥漫性腹膜内疾病（如卵巢癌或胰腺癌）的高度广泛和集中的临床前研究继续向前推进，以进行潜在的临床试验，但由于NCI的合作者反应不佳，计划使用212Pb的试验已转移到UAB。与FDA的ind前会议确定了在工业合作伙伴启动GMP生产时所需的毒性研究的相关问题。除了单独评价这些放射性核素与特异性单克隆抗体的疗效外，还将继续系统地研究放射性标记单克隆抗体的联合使用及其与化疗药物的联合使用。这项研究基于一种假设，即单一剂量的靶向放射性核素缺乏癌症治疗的合理基础，而联合治疗将显著增强治疗效果。结果表明，单剂量213Bi或212Pb结合临床相关抗体（如CC49(Delta)CH2、赫赛汀和现在的艾比妥），可以显著增加小鼠模型的中位预期寿命。212Pb联合吉西他滨治疗效果显著增强；212Pb和吉西他滨的分级给药提供了证据，表明优化药物组合和计划将延长生存期。将213Bi或212Pb与紫杉醇联合使用的研究显示，患者的生存期显著延长，且对给药计划有很强的依赖性，该研究最近在《临床癌症研究》（Clinical Cancer Research）上发表了一篇论文。也进行了类似的调查，评估联合卡铂或顺铂的影响。今年重复了用紫杉醇分离213Bi的研究。212pb标记的Erbitux（西妥昔单抗）进行了初步研究，以支持另一项0期111In成像试验，同时也为靶向多细胞表面受体的治疗性放射治疗奠定了基础，以解决与放射性标记的赫赛汀联合使用时的肿瘤异质性。第二种抗egfr抗体panitumumab在实验室进行了类似的研究，因为这种抗体与西妥昔单抗没有交叉反应，因此允许在联合治疗试验中使用所有3种抗体。到目前为止，几乎所有的研究结果都表明，212Pb的反应明显优于213Bi，这可能仅仅与半衰期有关。与Gius实验室(放射肿瘤学分部，CCR)在细胞水平上调查和定义损伤反应和修复的生物学机制，以及细胞生物学的遗传调控，以应对高let辐射的穿越，无论是单独的还是与化疗药物联合治疗。合作研究继续进行，提供试剂和/或专业知识，以促进校外研究人员快速完成这些研究的能力需要进行实验，以充分确定靶向放射治疗的实际临床影响。为此，该科继续与CCR代谢科和路德维希研究所（Andrew Scott）保持非常牢固和有效的合作关系，并将这一活动扩展到与UAB建立密切的合作关系，将212Pb转化为该放射性核素治疗弥漫性卵巢癌的第一个临床试验。

Tumor-associated monoclonal antibodies (mAbs) are therapeutic agents when utilized as selective carriers of cytotoxic agents to malignant cells. This hypothesis is tested in animal model systems with mAbs directed toward antigens associated with a variety of malignancies. The cytocidal agents employed are particle emitting radionuclides and their relative efficacy is evaluated in appropriate murine tumor xenograft model systems. The radionuclides chosen for study span the range of radionuclidic properties available thereby permitting the assay of the effects of emission energy, half-life, and type of emission. Current research continues to be focused on performing extensive pre-clinical studies with alpha-particle emitting radionuclides 212Pb, 213Bi, and 211At. Ongoing collaborative clinical trials employ the second generation bifunctional chelating agent 1B4M-DTPA (aka MX-DTPA or tiuxetan) for sequestering 90Y, however, nearly all of the collaborative clinical trials now employ the third-generation bifunctional chelating agent, CHX-A'' DTPA, for 111In, 90Y, 213Bi, and now potentially 177Lu. Studies initiated this year continue to validate the use of the CHX-A'' DTPA for use in positron emission tomography (PET) imaging with 86Y while that same established chelation chemistry for 213Bi continues to be employed in both pre-clinical and clinical studies. Pre-clinical evaluation of novel bifunctional chelating agents and linkers for targeted radiotherapy with isotopes of interest continues primarily in regards to refinements in conjugation chemistry options and radiolabeling improvements. These refinements stem from a combination of expansion to provide agents for peptide chemistry as well as for site-specific conjugation strategies that would be amenable for use with both radio-lanthanides and alpha-particle emitting radionuclides such as 213Bi. In parallel with these refinements, a novel bifunctional cross-bridged cyclam with an active ester moiety was developed for use with Cu-64 that should prove useful for both PET imaging and therapy. Additionally, novel linking chemistry for extant bifunctional chelating agents has been developed that is also amenable to peptide usage and even in use within peptide synthesizer instrumentation. Thus, many of the established agents of the Chemistry Section are now being extended to peptides and other small delivery vectors targeting receptors of interest such as affibodies. Studies with 211At that have been temporarily on hiatus after validation of the most stable 211At linker reagent, N-Me-SAPS, will be resumed later this calendar year to open a parallel investigation to those ongoing with other alpha emitters to treat disseminated intraperitoneal disease. The highly extensive and focused pre-clinical investigation into the use of both 212Bi and 212Pb continues for the treatment of disseminated intraperitoneal disease such as that arising from either ovarian cancer or pancreatic cancer continues to move forward towards a potential clinical trial, however the planned trial using 212Pb has been relocated to UAB due to unresponsive collaborators at the NCI. A pre-IND meeting with the FDA has defined the relevant issues regarding toxicity studies that are required while GMP manufacturing has been initiated by an industrial partner. In addition to evaluation of the efficacy of these radionuclides individually with specific mAbs, the use of combined radiolabeled mAbs, and their combinations with chemotherapeutics continues to be systematically investigated. This investigation rests on the hypothesis that single doses of a single, targeted radionuclide lack a rational basis for cancer therapy and that combined modality therapies will achieve significant therapeutic enhancements. Results have indicated that substantial increases in median life expectancy in murine models are possible with single doses of 213Bi or 212Pb conjugated to clinically relevant antibodies such as CC49(Delta)CH2, Herceptin, and now Erbitux. Use of 212Pb in combination with Gemcitabine showed impressive enhanced therapeutic efficacy; fractionated dosing of both 212Pb and Gemcitabine provided evidence that optimization of both drug combination and scheduling will result in extended survival. Studies combining administration of 213Bi or 212Pb with taxol demonstrated significant extension of survival with a very strong dependence on administration scheduling and were recently the topic of a publication in Clinical Cancer Research. A similar line of investigation assessing the impact of combination with carboplatin or cisplatin has also been performed. Fractionation studies of 213Bi with taxol were repeated this year. Preliminary studies with 212Pb-labeled Erbitux (cetuximab) were executed to support another Phase zero 111In imaging trial while also laying the groundwork for delivery of therapeutic radiation targeted to multiple cell surface receptors to address tumor heterogenicity when used in combination with radiolabeled Herceptin. A second anti-EGFR antibody, panitumumab, was similarly studied in the lab since this antibody is not cross-reactive with cetuximab thereby permitting use of all 3 antibodies in combination therapy trials. Results on almost all studies have so far indicated a significant superiority in response for 212Pb over 213Bi that may be solely related to half-life. Studies have been initiated in collaboration with the Gius lab (Radiation Oncology Branch, CCR) to investigate and define the biological mechanisms at the cellular level of both damage response and repair as well as genetic regulation of the cell biology in response to traversal of high-LET radiation both alone and in combination with treatment with chemotherapeutics Collaborative studies continue to be executed with either reagents and/or expertise being supplied to facilitate the ability of extramural researchers to expeditiously perform those experiments required to fully define the actual clinical impact of targeted radiation therapy. To this end, the Section continues to enjoy very strong and potent collaborative relationships with the Metabolism Branch, CCR and with the Ludwig Institute, (Andrew Scott) and has extended this activity to embrace a close collaborative relationship with UAB to translate 212Pb into the first clinical trial of this radionuclide for the treatment of disseminated ovarian cancer.