Anti-Mullerian Inhibiting Substance Type II Receptor (MISIIR) Immunoconjugates to

虽然在了解卵巢癌的生物学和改善治疗方面取得了进展，但迫切需要改进的诊断和治疗方法。抗体靶向肿瘤相关结构的能力可以提高对肿瘤的选择性识别和破坏。抗体工程的最新进展使得对抗体进行结构修饰以优化其肿瘤靶向和效应功能成为可能。例如，我们已经制备并鉴定了一种主要由抗原结合位点(Diabody)组成的针对HER2/neu的重组抗体衍生蛋白。Diabody是一种非共价连接的单链Fv(ScFv)二聚体，表现出优异的和 在治疗HER2/neu过表达的恶性肿瘤中的独特前景。然而，HER2/neu是 在卵巢癌中罕见的过度表达。因此，有必要考虑不同的抗原靶点，以有效地开发这种新的抗体结构形式的潜力。以干扰卵巢癌生长和生存信号的方式靶向受体是特别可取的。人类苗勒氏抑制物质受体是卵巢癌的候选靶抗原。这种受体在卵巢癌细胞系和从卵巢癌患者腹水中分离出来的细胞中有很大比例的表达。我们已经分离了MISIIR的胞外区(ECD)基因，并在哺乳动物细胞系中产生了ECD。我们假设，高亲和力的抗MISIIR分子将有效地靶向卵巢癌，这些分子将成为治疗放射性核素应用的有效载体。这项建议的目的是：1)开发人的Diabody分子特异性的胞外结构域的 目的：确定放射性标记的抗MISIIR Diabody分子的体内靶向和抗肿瘤特性；3)进行初步临床试验，以确定(124)放射性标记的抗MISIIR Diabody靶向治疗卵巢癌的敏感性和特异性。到拟议的资助期结束时，这些研究产生的数据将支持启动一项试点的第一阶段治疗试验，使用放射性标记的抗MISIIR糖尿病治疗卵巢癌。

While advances have been made in understanding the biology and improving the treatment of ovarian cancer, improved diagnostic and therapeutic approaches are urgently needed. The ability of antibodies to target defined tumor-related structures can improve the selective identification and destruction of tumors. Recent advances in antibody engineering make it possible to structurally modify antibodies to optimize their tumor targeting and effector functions. For example, we have prepared and characterized a recombinant antibody-derived protein consisting primarily of antigen-combining sites (diabody), that targets HER2/neu. This diabody is a non-covalently joined single-chain Fv (scFv)-based dimer that shows exceptional and unique promise in the therapy of HER2/neu overexpressing malignancies. However, HER2/neu is infrequently overexpressed in ovarian cancer. Accordingly, it is necessary to consider different antigen targets to effectively exploit the potential of this novel antibody structural format. It is particularly desirable to target receptors in a manner that disrupts signaling for ovarian cancer growth and survival. The human Mullerian inhibiting substance (MIS) receptor is an attractive candidate target antigen in ovarian cancer. This receptor is expressed in a large percentage of ovarian cancer cell lines and cells isolated from ascites fluid collected from ovarian cancer patients. We have isolated the gene for the MIS type II receptor (MISIIR) extracellular domain (ECD) and have produced the ECD in mammalian cell lines. We hypothesize that high-affinity anti-MISIIR diabodies will efficiently target ovarian cancer, and that these molecules will be effective delivery vehicles for therapeutic radionuclide applications. The aims of this proposal are: 1) To develop human diabody molecules specific for the extracellular domain of the MIS type II receptor; 2) To determine the in vivo targeting and anti-tumor properties of radiolabeled anti-MISIIR diabody molecules; 3) To perform pilot clinical trials that will determine the sensitivity and specificity of (124)I-radiolabeled anti-MISIIR diabody-based targeting in ovarian cancer. By the end of the proposed funding period the data generated by these studies will support the initiation of a pilot, Phase I therapy trial employing a radiolabeled anti-MISIIR diabody for the treatment of ovarian cancer.