STUDIES TO IMPROVE CANCER THERAPY WITH ANTIBODIES

利用抗体改善癌症治疗的研究

• 批准号: 6145982
• 负责人: GERALD L DENARDO
• 金额: $ 40万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-15 至 1999-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6145982
• 关键词: combination cancer therapy; human therapy evaluation; immunoconjugates; monoclonal antibody; neoplasm /cancer immunotherapy; neoplasm /cancer radionuclide therapy

This proposal is a competitive renewal for a Program grant whose purpose is to develop effective therapy for incurable B cell malignancies and breast adenocarcinoma using radiolabeled antibodies. Durable clinical responses have been achieved in the majority of 58 patients with B cell malignancies, primarily NHL, that were treated with Lym-1 and 20 patients with breast adenocarcinoma using primarily Chimeric L6 antibody. All of these patients were resistant to standard therapy. chimeric L6 showed profound biological activity that may have enhanced the radiation effect in the patients, but therapy was sometimes interrupted by an antiglobulin response. The efficacy of these radiolabeled antibodies is remarkable when one considers that they were used in isolation, and improvements could lead to cure of incurable disease. Enhancement strategies to improve the therapeutic index including various radionuclides and radiochemistries for conjugation, fractionation of therapy, agents to increase delivery to the tumor, immunoabsorption to decrease radiation to normal tissues, colony stimulating factors and stem cell marrow reconstitution were found to have merit. Of these factors we have chosen to focus on the radionuclide and radiochemistry to increase radiation to the malignancy, Interleukin-2 to increase tumor uptake and radiation, and stem cell marrow reconstitution to extend the maximum tolerated dose. Because state of the art macrocyclic chelates are available through Project 4, Project 1 proposes a Phase II trial of 67Cu-BAT-Lym-1 and 90Y- BAD-ChL6 with stem cell marrow reconstitution. Cyclosporin A will be used in Project to prevent antiglobulin response. The therapeutic index of 67 Cu-BAT-Lym-1 and 90Y-BAD-ChL6 is several times that of the corresponding 131I antibody because of tumor retention. Interleukin-2 is to be used to enhance tumor uptake in Project 1 and, if effective, will be used in Project 2. Similarly, strategies found to be effective in Project 2 will be added to the trials in Project 1. In addition to the development of macrocycles for 67 Cu, 111In and 90Y, and methods for site specific attachment to specific antibodies residues, Lym-1 has been sequenced and a single chain antibody prepared by genetic engineering in Project 4. this proposal includes generation of additional engineered constructs and their exploration as therapeutic agents. Strengths of the Program include an interdisciplinary group that has established their commitment and cohesiveness, and the clinical relevance of the proposed therapeutic agents. Projects 1 and 2 benefit from new constructs and radiochemistry generated in Project 4 and from opportunities for comparisons of the biology of breast cancer and B cell malignancies. Project 4 benefits from feedback of biologic and clinical information generated in Projects 1 and 2 for new constructs and radiochemistry. The information form this Program is relevant to the use of other conjugated and unconjugated antibodies.

该提案是计划赠款的竞争性更新 是为无法治愈的B细胞恶性肿瘤开发有效的疗法 乳腺癌使用放射性标记抗体。 耐用的临床 在大多数B细胞患者中，大多数人都达到了反应 由LYM-1和20患者治疗的恶性肿瘤，主要是NHL 与乳腺腺癌一起使用主要是嵌合L6抗体。 所有人 这些患者对标准疗法有抵抗力。 嵌合L6显示 可能增强辐射效应的深刻生物学活性 在患者中，但有时会通过抗球蛋白中断治疗 回复。 这些放射性标记抗体的功效非常明显 当人们认为它们是孤立使用的，并改进 可能导致治愈无法治愈的疾病。 增强策略 改善包括各种放射性核素的治疗指数和 偶联，治疗分馏，代理的放射性化学工具 增加对肿瘤的递送，免疫吸收以减少辐射 对于正常组织，菌落刺激因子和干细胞骨髓 发现重组有价值。 在这些因素中，我们选择了 专注于放射性核素和放射化学，以增加辐射到 恶性肿瘤，白介素2增加肿瘤的摄取和辐射，以及 干细胞骨髓重建以扩展最大耐受剂量。 因为可以通过 项目4项目1提出了67cu-bat-lym-1和90y-的II期试验 带有干细胞骨髓重建的坏chl6。 环孢菌素A将 用于预防抗球蛋白反应的项目。 治疗指数 在67个Cu-Bat-Lym-1和90y-Bad-Chl6中，有几倍 由于保留肿瘤，相应的131i抗体。 白介素2 用于增强项目1中的肿瘤吸收，如果有效， 将在项目2中使用。同样，发现有效的策略 在项目2中，项目1将添加到项目1中的试验中。 67 Cu，111in和90y的大环的发展，以及用于 位点特异性附着在特定抗体残基上，LYM-1一直是 通过基因工程制备的测序和单链抗体 项目4。该提案包括生成其他工程 构建及其作为治疗剂的探索。 优势 计划包括一个建立他们的跨学科小组 承诺和凝聚力以及提议的临床相关性 治疗剂。 项目1和2从新结构中受益， 项目4中产生的放射化学，从 比较乳腺癌和B细胞恶性肿瘤的生物学。 项目4从生物和临床信息的反馈中受益 在项目1和2中生成新的结构和放射化学。 这 信息表格该程序与其他共轭的使用有关 和未结合的抗体。