Anti-CD30 Radioimmunotherapy of Lymphoma

尽管霍奇金淋巴瘤是所有恶性肿瘤中治愈率最高的之一，但原发性难治性疾病和初始治疗后早期复发的疾病患者难以治愈。该项目的重点是开发抗CD 30抗体作为治疗CD 30+淋巴瘤（主要是霍奇金淋巴瘤）的放射免疫制剂。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，放射与联合化疗以非交叉耐药的方式发挥作用。CD 30是一种首先在霍奇金淋巴瘤上定义的抗原，是一种有吸引力的治疗靶点，目前正在用未修饰的人抗体、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CD 30构建体的放射免疫治疗，包括用于潜在内化抗原系统的适当放射性同位素。HeFi-1将作为第一个临床试验的抗体，使用放射性重金属结合材料，111/In用于成像/剂量测定，90 y用于治疗。该抗体已经准备好用于临床研究，并通过NCI-RAID资助提供。放射性金属与HeFi-1的组合应被证明是治疗的最佳选择，并将首次将抗CD 30抗体作为放射性金属的放射免疫治疗进行评估。这是内化抗原系统的重要特征，其中重金属将保持结合在细胞内， 与同位素在细胞内代谢时释放碘化抗体不同。目的2将集中于开发额外的抗CD 30抗体构建体，评估与不同CD 30簇结合的Ki-4抗体，以及比较三种治疗性同位素131/I、90 y、67 Cu。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。目的3将评估一系列针对CD 30的各种表位的抗CD 30抗体作为放射性同位素的载体，并探索将两种或多种抗体组合用于放射性配体的最佳内化的潜力。用免疫抑制剂控制CD 30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是利用分子工程技术构建最有前途的抗CD 30抗体，探索单链抗体二聚体（diabody）和微抗体（minibody）。

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.