CLINICAL TRIALS OF BIOLOGICAL RESPONSE MODIFIERS

该计划的目标是开发一种治疗方法， 使用生物活性人源化的转移性乳腺癌 与其他生物反应调节剂联合的放射免疫缀合物 (BRM的）。在本建议书中，我们计划将一组精选的BRM联合收割机组合起来， 以编程方式治疗晚期乳腺癌， 实现临床反应，同时评估可能的机制， 协同肿瘤细胞毒性。 这个项目的分子免疫学小组将寻求人性化 选择的MoAb，他们以前已经开发了定义的分子 与乳腺癌相关的靶点。MoAb BrE-3现已被人源化 （HuBrE-3），同时保留其高抗原结合亲和力。进一步 将关注对生物活动的控制， 由ADCC和CDC证明。选择用于临床的特异性单克隆抗体 研究将根据其可能加入的基础上选择， 治疗潜力即进一步增强体内效应细胞 激活、补体介导的肿瘤细胞溶解或对生长的影响 调节分子。药代动力学和辐射剂量学推导 定量成像将提供判断效果的方法 对这些方法的治疗指数和相关性进行了讨论 治疗反应。 这个项目的优势包括一个调查小组， 在临床放射免疫治疗和BRM方面取得的成就， 直接攻击了成功使用必须解决的问题 治疗实体瘤中描述的研究结果 这项利用人源化生物活性单克隆抗体的提议， 放射性结合物、干细胞生长因子和其他BRM持有的 显著的治疗潜力。这次调查将提供 一般适用于治疗其他 放射性标记的生物工程分子在联合治疗中的应用， 我们相信这种方法将导致显著的治疗反应， 耐受性良好的剂量水平。

The goal of this program is to develop a therapeutic approach for metastatic breast cancer using biologically active humanized radioimmunoconjugates combined with other biologic response modifiers (BRM's). In this proposal we plan to combine a select set of BRM's for therapy of advanced breast cancer in a programmed manner calculated to achieve clinical responses while evaluating possible mechanisms to achieve synergistic tumor cytotoxicity. The molecular immunology group in this program will seek to humanize selected MoAbs which they have previously developed to defined molecular targets associated with breast cancer. MoAb BrE-3, has now been humanized (HuBrE-3) while retaining its high antigen binding affinity. Further attention will be placed on control of such biologic activities as demonstrated by ADCC and CDC. The specific MoAb's chosen for clinical study will be selected on the basis of their possible addition to the therapeutic potential...i.e. further enhancement of in vivo effector cell activation, complement mediated tumor cytolysis or effect on growth regulating molecules. Pharmacokinetics and radiation dosimetry derived from quantitative imaging will provide the method for judging the effect of these approaches on the therapeutic index and correlation will be made with therapeutic response. Strengths of this project include an investigative team that has a record of accomplishments with clinical radioimmunotherapy and BRM's, and who has directly attacked the problems that must be resolved to successfully use this therapy for solid tumors. The results from the studies described in this proposal utilizing humanized biologically active MoAbs, advanced radioconjugates, stem cell growth factors and other BRM's holds significant therapeutic potential. This investigation will provide information that is generally applicable to treatment with other radiolabeled bioengineered molecules in combined therapeutic endeavors and we believe this approach will result in significant therapeutic response at well tolerated dose levels.