CLINICAL DEVELOPMENT OF 2B1 BISPECIFIC MONOCLONAL AB

非结合鼠单克隆抗体治疗人类恶性肿瘤 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性效应细胞结合 通过它们的Fc结构域，由于来自循环免疫球蛋白的竞争。 这限制了这些抗体集中宿主免疫的能力， 抗肿瘤反应。双特异性单克隆抗体（BsMAb）， 对肿瘤抗原和表位具有双重特异性， Fc-γ受体III（Fc-γ-RIII）免疫球蛋白Fcc结合结构域 通过大颗粒淋巴细胞触发肿瘤抗原特异性细胞毒性 (LGL)和巨噬细胞在存在竞争性人免疫球蛋白或 全血，并在scid中的人肿瘤异种移植模型中具有活性 小鼠一种这样的BsMAb，命名为2B 1，具有双重特异性， c-erbB 2蛋白的胞外结构域和Fc-γ- 正在进行的IA期试验将确定RIII的II期工作剂量， 这个BsMAb该BsMAb是检测中枢神经系统的合适试剂。 这项工作假设，即BsMAb治疗可以促进 相关细胞毒性效应细胞在肿瘤部位的蓄积， 治疗效果。这项建议的第一个具体目标是 确定2B 1 BsMAb治疗的疗效和2B 1 诱导肿瘤效应细胞浸润。为了实现这一目标， 一项在患有以下疾病的女性中静脉注射2B 1的IB/II期试验 将进行转移性乳腺癌。至少10名患者将 有活检可触及的疾病来解决肿瘤浸润问题， 至少有14名患者将有可测量的疾病来回答 功效考虑。第二个具体目标是增强BsMAb- 通过扩增该效应细胞群，靶向LGL向肿瘤的迁移 以及在以下的IA/IB期试验中改变毛细血管内皮渗透性： 2B 1加白细胞介素-2（IL-2），以允许选择性保留2B 1- 将LGL导向肿瘤部位。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2B 1和巨噬细胞集落刺激因子的IA/IB期试验中， 基础治疗。临床试验设计允许回顾性 比较所有三项临床试验中的肿瘤活检研究，以及 将产生关于每种治疗的相对效果的信息， 肿瘤相关效应细胞迁移或增殖程序 网站.在这些研究的结论中，2B 1治疗在 乳腺癌将是已知的，伴随治疗的影响， 其他生物制剂对选定的关键终点的作用将更好 明白这些研究将由一个财团进行， 调查人员在进行复杂，协作，早期 新生物制剂和策略的临床试验阶段。为 参与的研究者是生物反应的关键参与者 美国东部肿瘤协作组（ECOG）修改委员会， 2B 1的后续发展将发生在ECOG中。

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.