ENHANCED TREATMENT OF B CELL MALIGNANCIES WITH RADIOLABELED LYM-1 MAB

使用放射性标记的 LYM-1 MAB 增强 B 细胞恶性肿瘤的治疗

• 批准号: 6236980
• 负责人: GERALD L DENARDO
• 金额: $ 15.54万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-09 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6236980
• 关键词: B lymphocyte; antitumor antibody; athymic mouse; biological response modifiers; chelating agents; clinical trials; combination cancer therapy; copper; dosage; human subject; human therapy evaluation; immunoconjugates; immunomodulators; indium; interleukin 2; monoclonal antibody; neoplasm /cancer immunotherapy; neoplasm /cancer radionuclide therapy; nonHodgkin's lymphoma; pharmacokinetics; radiation therapy dosage; radionuclide imaging /scanning; radionuclides; radiopharmacology; radiotracer

the majority of non-Hodgkin's lymphomas (NHL) and chronic lymphocytic leukemias (CLL) are of B cell origin and many of these patients ultimately die from their disease despite standard therapy. Lym-1 is a monoclonal antibody that reacts with B cells specifically including malignant tissue from more than 80% of patients with NHL and 40% of patients with CLL of B cell origin. Durable clinical responses were observed in the majority of 58 patients with B cell malignancies, primarily NHL, that were treated with radiolabeled Lym-1. Toxicity was acceptable and thrombocytopenia was dose-limiting. Several patients developed inflammation over lesions that suggested a biologic response although Lym-1 alone has not proven therapeutic. The efficacy of radiolabeled Lym-1 in NHL is remarkable when one considers that it was used in isolation, and improvements could lead to cure of incurable disease. We examined a number of enhancement strategies to improve the therapeutic index including various radionuclides and radiochemistries for conjugation, effects of fractionation of therapy, agents to alter delivery to the tumor, and immunoabsorption to decrease radiation to normal tissues. While all of these strategies showed merit, we've chosen to focus on the radionuclide and radiochemistry, and Interleukin-2 (IL-2) during the proposed grant period because they were most promising. Observations on the pharmacokinetics and radiation dosimetry of 67 Cu or 90Y conjugated to Lym-1 with macrocyclic chelates specifically generated for these radionuclides in Project 3 indicated significant advantages for therapy. Because 67Cu-BAT-Lym-1 is retained in the malignancy, the radiation dose was several times greater than that from 131I-Lym-1 in patients. The MTD for 67Cu-BAT-Lym-1 was two doses each of 60 mCi/m2 given four weeks apart, and two of three patients responded to therapy. Studies in mice with human lymphoma showed that tumor uptake and radiation dose was increased two fold by IL-2 and suggested that response surface experimental designs were an efficient approach to studies of this type. Methods to be used include: 1) classical phase II clinical trial design for therapeutic agents in patients with malignant disease; 2) newer response surface designs for Il-2 enhancement; 3) quantitative imaging for pharmacokinetics and radiation dosimetry; and 4) tomographic imaging for tumor volume. Strengths of this project include an interdisciplinary group that has established their commitment and cohesiveness, and the clinical relevance of Lym-1 treatment. This project benefits from studies in Project 4 where new constructs and radiochemistry are generated and opportunities for comparisons of the biology and radiobiology with breast cancer in Project 2. Finally, Lym-1 or similar antibodies may be applicable to treatment of lymphomas associated with AIDS and other immunologic disorders.

大多数非霍奇金淋巴瘤（NHL）和慢性淋巴细胞 白血病（CLL）是B细胞的起源，其中许多患者 尽管有标准疗法，最终还是死于疾病。 Lym-1是a 与B细胞反应的单克隆抗体包括 超过80％的NHL患者和40％的恶性组织 B细胞起源的CLL患者。 持久的临床反应是 在大多数B细胞恶性肿瘤患者中，大多数观察到 主要是用放射性标记的LYM-1处理的NHL。 毒性是 可接受和血小板减少症是剂量限制的。 几个患者 对病变的炎症发生了，提示生物学反应 尽管仅淋巴结均未证明治疗。 当一个人在NHL中的放射性标记LYM-1的功效是显着的 认为它是孤立使用的，改进可能导致 治愈无法治愈的疾病。 我们检查了许多增强 改善治疗指数的策略包括各种 放射性核素和放射性化学，用于共轭的影响 治疗的分馏，改变肿瘤递送的药物以及 免疫吸收可减少对正常组织的辐射。 而全部 这些策略表现出优点，我们选择专注于放射性核素 在拟议的赠款期间 时期，因为它们是最有前途的。 观察到 67立方米或90年结合的药代动力学和辐射剂量法 Lym-1与大环螯合物专门生成 项目3中的放射性核素表明治疗具有显着优势。 因为在恶性肿瘤中保留了67cu-bat-lym-1，所以辐射剂量 比患者的131i-Lym-1大几倍。 MTD 对于67cu-bat-lym-1，给定四个星期的60 mci/m2中的两剂 除外，三名患者中有两名对治疗做出了反应。 在小鼠中的研究 与人淋巴瘤一起表明肿瘤摄取和辐射剂量为 IL-2增加了两倍，并建议响应表面 实验设计是对此类研究的有效方法。 要使用的方法包括：1）经典II期临床试验设计 用于恶性疾病患者的治疗剂； 2）较新 IL-2增强的响应表面设计； 3）定量成像 用于药代动力学和辐射剂量法； 4）层析成像 用于肿瘤体积。 该项目的优势包括跨学科 建立了他们的承诺和凝聚力的团体，以及 LYM-1治疗的临床相关性。 这个项目从中受益 在项目4中的研究，新的结构和放射化学是 生成和比较生物学的机会 项目2中的乳腺癌放射生物学。最后，Lym-1或类似 抗体可能适用于与 艾滋病和其他免疫疾病。