CLINICAL DEVELOPMENT OF 2B1 BISPECIFIC MONOCLONAL AB

2B1 双特异性单克隆抗体的临床开发

• 批准号: 2098960
• 负责人: Louis M. Weiner
• 金额: $ 21.17万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-10 至 1997-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2098960
• 关键词: antibody receptor; biological response modifiers; biopsy; clinical trials; cooperative study; cytotoxic T lymphocyte; dosage; epitope mapping; female; human subject; human therapy evaluation; immunoglobulin structure; interleukin 2; monoclonal antibody; neoplasm /cancer immunotherapy; neoplasm /cancer therapy; phagocytes; tumor antigens

Treatment of human malignancies with unconjugated murine monoclonal antibodies infrequently leads to meaningful clinical responses, possibly because these antibodies do not bind to cytotoxic effector cells in vivo via their Fc domains due to competition from circulating immunoglobulins. This limits the ability of these antibodies to focus a host immune response against tumor. Bispecific monoclonal antibodies (BsMAb) which have dual specificity for tumor antigens and epitopes outside the immunoglobulin Fcc binding domain of Fc-gamma receptor III (Fc-gamma-RIII) trigger tumor antigen-specific cytotoxicity by large granular lymphocytes (LGL) and macrophages in the presence of competing human immunoglobulin or whole blood, and possess activity in human tumor xenograft models in scid mice. One such BsMAb, designated 2B1, has dual specificity for the extracellular domain of c-erbB2 protein and the 3G8 epitope of Fc-gamma- RIII; an ongoing Phase IA trial will identify the Phase II working dose of this BsMAb. This BsMAb is a suitable reagent to test the central hypothesis of this work, which is that BsMAb therapy can promote the accumulation of relevant cytotoxic effector cells at tumor sites, with therapeutic results. The first specific aim of this proposal is to determine the efficacy of 2B1 BsMAb therapy and the ability of 2B1 to induce effector cell infiltration of tumor. To accomplish this objective, a Phase IB/II trial of intravenously administered 2B1 in women with metastatic breast cancer will be conducted. A minimum of 10 patients will have biopsy-accessible disease to address the tumor infiltration question, and a minimum of 14 patients will have measurable disease to answer the efficacy considerations. The second specific aim is to enhance BsMAb- targeted LGL migration to tumor by expanding this effector cell population and modifying capillary endothelial permeability in a Phase IA/lB trial of 2B1 plus interleukin-2 (lL-2) to permit the selective retention of 2B1- directed LGL at tumor sites. The third specific aim is to expand and utilize mononuclear phagocytes and Fc-gamma-RIII-expressing effector cells in a Phase IA/IB trial of 2B1 and macrophage-colony stimulating factor- based treatment. The clinical trial designs permit the retrospective comparisons of the tumor biopsy studies in all three clinical trials, and will yield information about the relative effects of each treatment program on relevant effector cell migration or proliferation at tumor sites. At the conclusion of these studies, the efficacy of 2B1 therapy in breast cancer will be known, and the effects of concomitant therapy with other biologic agents on selected critical endpoints will be better understood. These studies will be performed by a consortium of investigators experienced in the conduct of complex, collaborative, early phase clinical trials of novel biologic agents and strategies. As the involved investigators are key participants in the Biologic Response Modifiers Committee of the Eastern Cooperative Oncology Group (ECOG), subsequent development of 2B1 will occur with the ECOG.

非偶联鼠单抗治疗人类恶性肿瘤的研究 抗体很少导致有意义的临床反应，可能 因为这些抗体在体内不与细胞毒效应细胞结合 由于循环免疫球蛋白的竞争，通过它们的Fc结构域。 这限制了这些抗体集中宿主免疫的能力。 对肿瘤的反应。双特异性单抗(BsMAb) 对肿瘤抗原和表位具有双重特异性 Fc-γ受体III免疫球蛋白FCC结合区(Fc-Gamma-RIII) 大颗粒淋巴细胞触发肿瘤抗原特异性细胞毒作用 (LGL)和巨噬细胞在竞争的人免疫球蛋白或 全血，并在SCID人肿瘤移植模型中具有活性 老鼠。其中一种BsMAb，命名为2B1，具有双重特异性 C-erbB2蛋白的胞外区和Fc-γ的3G8表位 正在进行的IA阶段试验将确定以下物质的第二阶段工作剂量 这个BsMAb。此BsMAb是一种适合检测中枢神经系统的试剂。 这项工作的假设是，BsMAb疗法可以促进 相关的细胞毒效应细胞在肿瘤部位聚集， 治疗效果。这项建议的第一个具体目标是 确定2B1 BsMAb治疗的疗效和2B1的能力 诱导效应细胞对肿瘤的侵袭。为了实现这一目标， 静脉给药2B1治疗女性卵巢癌的IB/II期试验 将进行转移性乳腺癌。至少有10名患者将 有活组织检查可及的疾病来解决肿瘤的渗透问题， 至少有14名患者将有可测量的疾病来回答 功效方面的考虑。第二个具体目标是增强BsMAb- 扩增LGL效应细胞群向肿瘤的靶向迁移 以及在IA/Lb期试验中修改毛细血管内皮细胞通透性 2B1加白介素2(IL-2)，以允许选择性保留2B1- 将LGL定向到肿瘤部位。第三个具体目标是扩大和 利用单核吞噬细胞和表达Fc-γ-RIII的效应细胞 在2B1和巨噬细胞集落刺激因子的IA/IB期试验中- 以治疗为基础。临床试验设计允许回顾 所有三个临床试验中肿瘤活检研究的比较，以及 将提供有关每种治疗方法的相对效果的信息 肿瘤相关效应细胞迁移或增殖计划 网站。在这些研究的结论中，2B1疗法的疗效 乳腺癌将会为人所知，同时治疗的效果与 在选定的关键终点上使用其他生物制剂会更好 明白了。这些研究将由一个财团进行 调查人员在复杂、协作、早期的行为中经验丰富 新型生物制剂和策略的阶段性临床试验。作为 相关研究人员是生物反应的关键参与者 东方合作肿瘤学小组(ECOG)修饰剂委员会， 2B1的后续开发将与ECOG一起进行。