Single Chelator-Minibody Conjugate for PET and Therapy Radionuclides

用于 PET 和治疗放射性核素的单螯合剂-微型抗体缀合物

• 批准号: 10325851
• 负责人: Darren J Magda
• 金额: $ 25.2万
• 依托单位: LUMIPHORE, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10325851
• 关键词: Affinity; Alpha Particles; Antibodies; Beta Particle; Binding; Biodistribution; Biologic Development; Biological; Biological Assay; Biological Markers; Bone Marrow Suppression; Buffers; CWR22Rv1; Cations; Cell Surface Proteins; Chelating Agents; Chemicals; Chemistry; Clinical; Clinical Research; Clinical Trials; Complex; Detection; Development; Dipeptides; Exclusion; Exhibits; FOLH1 gene; Funding; Goals; Half-Life; High Pressure Liquid Chromatography; Human; ITGAM gene; Image; In Vitro; Isotopes; J591 Monoclonal Antibody; Kinetics; Label; Lacrimal gland structure; Lead; Left; Lesion; Macrocyclic Compounds; Malignant neoplasm of prostate; Measures; Metastatic Prostate Cancer; Modeling; Mus; Myeloid Cells; PC3 cell line; Patient Monitoring; Patient Selection; Patients; Pentetic Acid; Performance; Phase; Phase II Clinical Trials; Positron; Positron-Emission Tomography; Property; Prostatic Neoplasms; Radiation therapy; Radioactive; Radioimmunoconjugate; Radioisotopes; Radiolabeled; Radionuclide therapy; Radiopharmaceuticals; Research; Salivary Glands; Salvage Therapy; Serum; Small Business Innovation Research Grant; Structure of base of prostate; Temperature; Therapeutic Uses; Time; Toxic effect; Urea; Xenograft Model; analog; animal-assisted therapy; antibody conjugate; base; cancer therapy; clinical development; dosimetry; efficacy study; efficacy trial; imaging agent; improved; inhibitor/antagonist; innovation; novel; overexpression; patient response; peptide analog; prostate cancer cell; research clinical testing; single photon emission computed tomography; small molecule; subcutaneous; success; theranostics; tumor; uptake

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.

抽象的 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) 药物来治疗癌症 通过单一螯合剂-微型抗体缀合物前体。 这里描述的新型治疗诊断剂采用了一种螯合剂 Lumi804，它可以快速且有效地 稳定螯合最广泛使用的抗体正电子发射体（Zr-89）和最广泛的 使用治疗性 β 发射放射性核素 (Lu-177) 和 α 发射同位素 (Th-227) 目前正在进行多项I期疗效试验的临床评估。据我们所知， 没有螯合剂-抗体或螯合剂-微型抗体缀合物正在进行人体试验或使用 临床上可在室内快速用 Zr-89（PET 成像）和 Lu-177（TRT）进行标记 温度。 基于二肽脲基序的小分子肽类似物，例如 F-18-PSMA-1007 或 Ga-68-PSMA-11 最近改善了前列腺癌的成像，以及类似物，例如 Lu-177-PSMA-617 和 Ac-225-PSMA-617 在患者中显示出显着疗效。然而， 使用 Lu-177-PSMA-617 治疗的患者经常复发，而使用 Ac-225-PSMA- 进行挽救治疗 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，但可能导致骨髓抑制 延长抗体的生物半衰期。 Zr-89-DFO-IAB2M 微型机身已 在 I 期临床研究中进行评估，发现唾液腺定位较低，而 生物半衰期比相应的 Zr-89-DFO-J591 短得多 抗体缀合物。 SBIR 第一阶段项目中拟议的研究将开发 合成并评估新型 Zr-89、Lu-177 和 Th-227 标记的抗 前列腺特异性膜抗原 (PSMA) 完整微型抗体构建体，利用单个 适用于所有三种放射性金属的螯合剂，用于病变检测、治疗和监测患者 对放射性核素治疗的反应。这些研究将使第二阶段的开发成为可能 第一种将正电子、β粒子和α粒子辐射靶向 PSMA 的治疗诊断剂 表达肿瘤。