Engineered anti-PSCA antibodies for immunoPET and targeted therapy of pancreatic cancer

胰腺癌仍然是最致命的实体瘤之一，这是由于诊断晚和高概率的并发症。 转移性扩散需要有效的新的系统性治疗，以改善患者的结局。 靶向放射性核素治疗已被证明是有效的癌症治疗，特别是177 Lu的成功。 在神经内分泌肿瘤中，包括胰腺肿瘤。前列腺干细胞抗原（PSCA） 在60-80%的胰腺癌中上调，使其成为抗体导向的靶点。 疗法工程化抗体片段A2 scFv-Fc 2 DM已被专门设计用于优化 在胰腺癌中递送治疗性放射性核素。它是基于人源化，高亲和力抗PSCA 抗体，并含有Fc突变，经工程改造以促进通过肝胆途径的快速血液清除。作为 因此，对关键器官/组织（骨髓和肾脏）的辐射剂量最小化，从而能够有效输送 发射α或β放射性核素的肿瘤。在目标1中，将在小鼠中进行生物分布研究 模型，以确认预期的肿瘤靶向和肝脏清除。正式的剂量估计将是 制备用于治疗的用177 Lu或225 Ac放射性标记的scFv-Fc 2 DM。目标2将探索潜力 抗PSCA scFv-Fc 2 DM在胰腺癌小鼠模型（包括皮下移植）中的功效 人胰腺肿瘤细胞的异种移植物，huPSCA敲入小鼠中KPC-PSCA肿瘤的同基因模型， 和患者来源的胰腺肿瘤异种移植物模型。α-发射体的相对功效和毒性 将对225 Ac和β-发射体177 Lu进行分析，以便为未来的临床治疗研究做准备。在目标3中， 将进行抗PSCA scFv-Fc 2 DM的临床生产和偶联，进行测试，并进行抗PSCA scFv-Fc 2 DM的临床试验。 IND存档。最后，在目标4中，我们将使用64 Cu-DOTA-抗PSCA scFv进行首次人体成像研究。 Fc 2 DM在晚期胰腺癌患者中的作用，以评估其靶向和清除特性， 这种新型工程抗体片段的潜在辐射剂量递送。临床结果 免疫PET研究将是指导放射免疫治疗剂未来发展的核心， 在胰腺癌的治疗诊断方法中实施。

Pancreatic cancer remains among the most lethal of solid tumors, due to late diagnosis and a high probability of metastatic spread. Effective new systemic treatments are needed in order to improve outcomes in patients. Targeted radionuclide therapy has demonstrated effectiveness cancer therapy, notably with the success of 177Lu- dotatate in neuroendocrine tumors including those of the pancreas. Prostate Stem Cell Antigen (PSCA) is upregulated in 60-80% of pancreatic adenocarcinomas, making it a promising target for antibody-directed therapy. An engineered antibody fragment, the A2 scFv-Fc2 DM has been specifically designed for optimized delivery of therapeutic radionucides in pancreatic cancer. It is based on a humanized, high-affinity anti-PSCA antibody, and contains Fc mutations engineered to foster rapid blood clearance via the hepatobiliary route. As a result, radiation dose to key organs/tissues (bone marrow and kidney) is minimized, enabling effective delivery of an alpha- or beta-emitting radionuclide to tumors. In Aim 1, biodistribution studies will be undertaken in mouse models, in order to confirm the expected tumor targeting and hepatic clearance. Formal dose estimations will be made for the scFv-Fc2 DM radiolabeled with either 177Lu or 225Ac for therapy. Aim 2 will explore the potential efficacy of the anti-PSCA scFv-Fc2 DM in mouse models of pancreatic cancer, including subcutaneous xenografts of human pancreatic tumor cells, a syngeneic model of KPC-PSCA tumors in huPSCA knock-in mice, and patient-derived pancreatic tumor xenograft models. The relative efficacies and toxicities of the alpha-emitter 225Ac and beta-emitter 177Lu will be analyzed in order to prepare for future clinical therapy studies. In Aim 3, clinical production and conjugation of the anti-PSCA scFv-Fc2 DM will be performed, testing conducted, and an IND filed. Finally, in Aim 4 we will conduct a first-in-human imaging study using 64Cu-DOTA-anti-PSCA scFv- Fc2 DM in patients with advanced pancreatic cancer, to evaluate the targeting, and clearance properties and potential radiation dose delivery of this novel engineered antibody fragment. Results from this clinical immunoPET study will be central to guiding future development of a radioimmunotherapy agent that can be implemented in a theranostic approach to pancreatic cancer.