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.

摘要 这项SBIR的总体目标是开发一种创新的治疗药物，用于成像和 结合PET成像和靶向放射性核素治疗(TRT)药物治疗癌症 通过单一的螯合剂-微体偶联前驱体。 这里描述的新型治疗药物使用了一种名为Lumi804的螯合剂，它可以快速和 稳定螯合最广泛使用的抗体正电子发射体(Zr-89)和最广泛的正电子发射体 使用治疗性贝塔发射放射性核素(Lu-177)和阿尔法发射同位素(Th-227) 目前正在进行多个I期疗效试验的临床评估。据我们所知， 目前还没有用于人体试验或使用的螯合剂-抗体或螯合剂-微体结合物。 临床上，可在房间内快速标记Zr-89(PET成像)和Lu-177(TRT) 温度。 基于二肽尿素基序的小分子多肽类似物，如F-18-PSMA-1007或 GA-68-PSMA-11最近改善了前列腺癌的成像，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， 用Lu-177-PSMA-617治疗的患者经常复发，而用Ac-225-PSMA-617进行抢救治疗- 617虽然有效，但由于唾液腺毒性而有限。放射性标记抗体的使用已经 已被证明可以避免唾液腺的定位，但可能会导致骨髓抑制 抗体的生物半衰期更长。Zr-89-DFO-IAB2M微型体已经被 在I期临床研究中进行评估，发现显示低唾液腺定位，而 表现出比相应的Zr-89-DFO-J591生物半衰期短得多的生物半衰期 抗体结合物。这项SBIR第一期工程的拟议研究将发展 新型Zr-89、Lu-177、Th-227标记抗癌药物的合成及性能评价 完整的前列腺特异性膜抗原(PSMA)微体构造，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。这些研究将有助于在第二阶段的发展 第一种用于靶向PSMA的正电子、β粒子和α粒子辐射的透声剂 表现为肿瘤。