Anti-CD30 Radioimmunotherapy of Lymphoma

淋巴瘤的抗CD30放射免疫治疗

• 批准号: 7124741
• 负责人: ANDREW A. RAUBITSCHEK
• 金额: $ 15.48万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7124741
• 关键词: CD antigens; Hodgkin' s disease; antibody specificity; antineoplastics; clinical research; clinical trial phase I; clinical trial phase II; combination cancer therapy; computed axial tomography; hematopoietic stem cells; hematopoietic tissue transplantation; human subject; human therapy evaluation; hybrid antibody; immunologic substance development /preparation; metalloendopeptidases; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer radioimmunotherapy; neoplasm /cancer relapse /recurrence; nonHodgkin' s lymphoma; patient oriented research; prognosis; radiation therapy dosage; radionuclides; therapy adverse effect; tissue /cell culture

Although Hodgkin's Lymphomas have one of the highest cure rates of any malignancy, patients with primary refractory disease and disease which relapses early after initial therapy are difficult to cure. This project is focused on the development of Anti-CD30 antibodies as a radioimmunotherapeutic for the treatment of CD30+ lymphomas, primarily Hodgkin's Lymphoma. Radioimmunotherapy offers an attractive therapeutic option, administering targeted radiation to sites of disease. Hodgkin's Lymphoma is generally radiosensitive and radiation exerts its action in a non-cross resistant manner with combination chemotherapy. CD30, an antigen which was first defined on Hodgkin's Lymphoma is an attractive target for therapeutics and is currently being evaluated in trials with unmodified human antibodies, immunotoxins, and radioimmunotherapy. This proposal will focus on Radioimmunotherapy using optimal anti-CD30 constructs including appropriate radioisotopes for a potentially internalizing antigen system. HeFi-1 will be the antibody for the first clinical trial, using radio heavy metal conjugated material, 111/In for the imaging/dosimetry and 90y for the therapy. The antibody is already prepared for clinical studies and is supplied through a NCI-RAID grant. The combination of radiometal with HeFi-1 should prove optimal for therapy and will represent the first time an anti-CD30 antibody will be evaluated as a radioimmunotherapeutic with a radiometal. This is an important feature for an internalizing antigen system where the heavy metal will remain bound intracellularly, in distinction from iodinated antibodies where isotope is released on intracellular metabolism. Aim 2 will focus on the development of additional anti-CD30 antibody constructs, evaluating Ki-4 antibody which binds to a different CD30 cluster, as well as comparing three therapeutic isotopes, 131/I,90y, 67Cu. Ki-4 has been used in clinical trials in Germany and a cell bank has been transferred to COH for further development. Aim 3 will evaluate a series of anti-CD30 antibodies directed at the various epitopes of CD30 as carriers of radioisotopes and explore the potential of combining two or more antibodies for optimal internalization of the radioligand. The potential of controlling the shedding of CD30 from the surface of the tumor cells with metalloproteinase inhibitors will also be explored. Aim 4 will focus on the molecular engineering of the most promising anti-CD30 antibody as an optimal radioimmunotherapeutic exploring the scFv dimers(diabody) as well as minibody format.

尽管霍奇金淋巴瘤是治愈率最高的恶性肿瘤之一，但患有原发性难治性疾病和初次治疗后早期复发的患者很难治愈。该项目的重点是开发抗 CD30 抗体作为放射免疫疗法，用于治疗 CD30+ 淋巴瘤，主要是霍奇金淋巴瘤。放射免疫疗法提供了一种有吸引力的治疗选择，对疾病部位进行有针对性的放射治疗。霍奇金淋巴瘤通常对放射敏感，并且放射以与联合化疗无交叉耐药的方式发挥其作用。 CD30 是一种首次在霍奇金淋巴瘤中定义的抗原，是一个有吸引力的治疗靶标，目前正在使用未经修饰的人类抗体、免疫毒素和放射免疫疗法进行试验评估。该提案将重点关注使用最佳抗 CD30 构建体进行放射免疫治疗，包括用于潜在内化抗原系统的适当放射性同位素。 HeFi-1将是第一个临床试验的抗体，使用放射性重金属缀合材料，111/In用于成像/剂量测定，90y用于治疗。该抗体已准备好用于临床研究，并由 NCI-RAID 拨款提供。放射性金属与 HeFi-1 的组合应该被证明是最佳的治疗方法，并且将代表抗 CD30 抗体首次被评估为放射性金属的放射免疫治疗剂。这是内化抗原系统的一个重要特征，其中重金属将保持在细胞内结合， 与碘化抗体不同，碘化抗体在细胞内代谢时释放同位素。目标 2 将重点开发其他抗 CD30 抗体构建体，评估与不同 CD30 簇结合的 Ki-4 抗体，以及比较三种治疗同位素 131/I、90y、67Cu。 Ki-4已在德国用于临床试验，细胞库已转移至COH进行进一步开发。目标 3 将评估一系列针对 CD30 各种表位的抗 CD30 抗体作为放射性同位素的载体，并探索组合两种或多种抗体以实现放射性配体最佳内化的潜力。控制 CD30 从肿瘤细胞表面脱落的潜力 金属蛋白酶抑制剂也将被探索。目标 4 将重点关注最有前途的抗 CD30 抗体的分子工程，作为探索 scFv 二聚体（双抗体）以及微型抗体形式的最佳放射免疫治疗方法。