Anti-CD30 Radioimmunotherapy of Lymphoma

虽然霍奇金淋巴瘤的治愈率是所有恶性肿瘤中最高的之一，但患有原发难治性疾病和在最初治疗后早期复发的患者很难治愈。本项目致力于开发抗CD30抗体作为治疗CD30+淋巴瘤的放射免疫疗法，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，对疾病部位进行靶向放射治疗。霍奇金淋巴瘤通常对放射敏感，放射通过联合化疗以非交叉耐药的方式发挥作用。CD30是一种最先定义在霍奇金淋巴瘤上的抗原，是一个有吸引力的治疗靶点，目前正在用未经修饰的人类抗体、免疫毒素和放射免疫疗法进行评估。这项建议将重点放在使用最佳的抗CD30结构的放射免疫治疗，包括潜在内化抗原系统的适当放射性同位素。HEFI-1将作为第一次临床试验的抗体，使用放射性重金属结合材料，111/in用于成像/剂量学，90Y用于治疗。该抗体已经准备好用于临床研究，并通过NCI-Raid赠款提供。放射金属与HEFI-1的结合将被证明是治疗的最佳组合，并将代表着抗CD30抗体将首次被评估为具有放射金属的放射免疫治疗。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，碘化抗体释放的同位素是细胞内的新陈代谢。目的2将专注于开发更多的抗CD30抗体构建体，评估与不同CD30簇结合的Ki-4抗体，以及比较三种治疗性同位素131/I，90Y，67Cu.KI-4已经在德国用于临床试验，一个细胞库已经转移到COH进行进一步开发。目的3将评估针对CD30的不同表位作为放射性同位素载体的一系列抗CD30抗体，并探索结合两种或两种以上抗体以优化放射性配基内化的可能性。抑制CD30从肿瘤细胞表面脱落的可能性 还将探索金属蛋白酶抑制剂。目的4将侧重于最有前景的抗CD30抗体的分子工程，作为最佳的放射免疫治疗，探索单链抗体二聚体(Diabody)以及微体形式。

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.