Single Chelator-Minibody Conjugate for PET and Therapy Radionuclides

摘要 该SBIR的总体目标是开发一种创新的治疗诊断剂，用于成像和 通过结合PET成像和靶向放射性核素治疗（TRT）剂治疗癌症 通过单个螯合剂-微抗体缀合物前体。 本文所述的新型治疗诊断剂采用螯合剂Lumi 804，其可以快速且 稳定地螯合用于抗体的最广泛使用的正电子发射体（Zr-89）和用于抗体的最广泛使用的正电子发射体。 使用治疗性β放射性核素（Lu-177）和α放射性同位素（Th-227） 目前正在多个I期疗效试验中进行临床评价。据我们所知， 没有在人体试验中或使用的螯合剂-抗体或螯合剂-微抗体缀合物 临床上可以在室温下快速用Zr-89（PET成像）和Lu-177（TRT）标记 温度 基于二肽脲基序的小分子肽类似物，如F-18-PSMA-1007或 Ga-68-PSMA-11最近改善了前列腺癌的成像，并且类似物如 Lu-177-PSMA-617和Ac-225-PSMA-617在患者中显示出显著的疗效。然而，在这方面， 用Lu-177-PSMA-617治疗的患者经常复发，而用Ac-225-PSMA-617治疗的挽救治疗通常复发。 617虽然有效，但由于唾液腺毒性而受到限制。放射性标记抗体的使用 已被证明可以避免唾液腺定位，但由于 抗体的生物半衰期更长。Zr-89-DFO-IAB 2 M微型机身已被 在I期临床研究中进行了评价，发现显示低唾液腺定位， 其生物半衰期比相应的Zr-89-DFO-J591短得多 抗体偶联物。SBIR第一阶段项目的拟议研究将开发 合成了一种新型的Zr-89，Lu-177和Th-227标记的抗- 前列腺特异性膜抗原（PSMA）完整微抗体构建体，利用单个 螯合剂，适用于所有三种放射性金属，用于病变检测、治疗和监测患者 对放射性核素治疗的反应。这些研究将有助于在第二阶段发展 将正电子、β粒子和α粒子辐射靶向PSMA的第一治疗诊断剂 表达肿瘤。

Abstract The overall goal of this SBIR is to develop an innovative theranostic agent for imaging and treatment of cancer, by combining PET imaging and targeted radionuclide therapy (TRT) agents via a single chelator-minibody conjugate precursor. The novel theranostic agent described here employs a chelator, Lumi804, that can quickly and stably chelate the most widely used positron emitter for antibodies (Zr-89) and the most widely used therapeutic beta-emitting radionuclide (Lu-177), and an alpha emitting isotope (Th-227) currently undergoing clinical evaluation in multiple phase I efficacy trials. To our knowledge, there are no chelator-antibody or chelator-minibody conjugates that are in human trials or used clinically that can be labeled with both Zr-89 (PET imaging) and Lu-177 (TRT) quickly at room temperature. Small molecule peptide analogues based on a dipeptide urea motif such as F-18-PSMA-1007 or Ga-68-PSMA-11 have recently improved imaging of prostate cancer, and analogues such as Lu-177-PSMA-617 and Ac-225-PSMA-617 are showing significant efficacy in patients. However, patients treated with Lu-177-PSMA-617 often recur, and salvage therapy with Ac-225-PSMA- 617, while effective, is limited due to salivary gland toxicity. Use of radiolabeled antibodies has been shown to avoid salivary gland localization, but can lead to bone marrow suppression due to the longer biological half-life of antibodies. The Zr-89-DFO-IAB2M minibody has been evaluated in Phase I clinical study and found to display low salivary gland localization while exhibiting a biological half-life that is much shorter than the corresponding Zr-89-DFO-J591 antibody conjugate. The proposed research in this SBIR Phase I project will develop the synthesis and evaluate the performance of a novel Zr-89, Lu-177, and Th-227 labeled anti- prostate specific membrane antigen (PSMA) intact minibody construct, leveraging a single chelator suitable for all three radiometals, for lesion detection, treatment, and monitoring patient response to radionuclide therapy. These studies will enable the development in Phase II of the first theranostic agent to target positron, beta particle, and alpha particle radiation to PSMA expressing tumors.