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

胰腺癌仍然是最致命的实体肿瘤之一，因为诊断较晚，而且 转移性扩散。为了改善患者的预后，需要有效的新的系统治疗。 靶向放射性核素疗法已经证明了癌症治疗的有效性，特别是177Lu- 神经内分泌肿瘤中的DOATATE，包括胰腺肿瘤。前列腺干细胞抗原(PSCA)是 在60%-80%的胰腺癌中表达上调，使其成为抗体导向的有希望的靶点 心理治疗。作为一种工程抗体片段，A2 scFv-FC2 DM是专门为优化而设计的 治疗性放射性核素在胰腺癌中的应用。它是基于人性化的、高亲和力的抗PSCA 抗体，并包含Fc突变，旨在通过肝胆途径促进血液快速清除。作为一名 结果，关键器官/组织(骨髓和肾脏)的辐射剂量被降至最低，从而能够有效地传递 向肿瘤发射的阿尔法或贝塔放射性核素。在目标1中，将在小鼠身上进行生物分布研究 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 用于放射标记177Lu或225Ac的ScFv-FC2 DM治疗。目标2将探索潜在的 抗PSCA单链抗体FC2 DM对小鼠胰腺癌皮下移植瘤的治疗作用 人胰腺肿瘤细胞的异种移植，敲除小鼠KPC-PSCA肿瘤的同基因模型， 和患者来源的胰腺肿瘤异种移植模型。阿尔法发射体的相对有效性和毒性 将对225Ac和β-发射体177Lu进行分析，为未来的临床治疗研究做准备。在《目标3》中， 将进行抗PSCA单链抗体-FC2 DM的临床生产和偶联，进行测试，并 IND备案。最后，在目标4中，我们将使用64CuDOTA-抗PSCA单链抗体进行首次人体成像研究。 FC2 DM在晚期胰腺癌患者中的应用，以评估靶向性、清除性和 这种新型工程抗体片段的潜在辐射剂量传递。这项临床试验的结果 免疫PET研究将是指导未来放射免疫治疗剂开发的核心，这种放射免疫治疗剂可以 在胰腺癌的治疗方法中实施。

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.