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。抗体靶向确定的肿瘤相关结构的能力可以改善肿瘤的选择性鉴定和破坏。抗体工程的最新进展使得在结构上修饰抗体以优化其肿瘤靶向和效应器功能成为可能。例如，我们已经制备并表征了主要由靶向HER 2/neu的抗原结合位点（双抗体）组成的重组抗体衍生蛋白。该双抗体是基于非共价连接的单链Fv（scFv）的二聚体，其显示出优异的和特异的免疫原性。 在HER 2/neu过表达恶性肿瘤的治疗中具有独特的前景。HER 2/neu是 在卵巢癌中很少过表达。因此，有必要考虑不同的抗原靶标以有效地利用这种新型抗体结构形式的潜力。特别期望以破坏卵巢癌生长和存活的信号传导的方式靶向受体。人苗勒管抑制物质（MIS）受体是卵巢癌的一个有吸引力的候选靶抗原。这种受体在大部分卵巢癌细胞系和从卵巢癌患者收集的腹水中分离的细胞中表达。我们已经分离了MIS II型受体（MISIR）细胞外结构域（ECD）的基因，并在哺乳动物细胞系中产生了ECD。我们假设高亲和力的抗MISIR双抗体将有效地靶向卵巢癌，并且这些分子将是治疗性放射性核素应用的有效递送载体。本提案的目的是：1）开发特异性针对人源性双抗体的细胞外结构域的人源性双抗体分子。 MIS Ⅱ型受体; 2）确定放射性标记的抗MISIR双抗体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）I-放射性标记的基于抗MISIR双抗体的靶向在卵巢癌中的灵敏度和特异性。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I期治疗试验，该试验采用放射性标记的抗MISIR双抗体治疗卵巢癌。

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.