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

基本信息

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
项目类别：
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

项目摘要

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theranotic剂，以进行成像和通过将PET成像和靶向放射性核素治疗（TRT）剂结合使用癌症的治疗通过单个螯合剂微骨共轭前体。此处描述的新颖的Theranostic剂采用螯合剂Lumi804，可以迅速而稳定的螯合物最广泛使用的抗体发射极（ZR-89）和最广泛的使用的治疗性β发射放射性核素（LU-177）和α发射同位素（TH-227）目前在多个I期功效试验中接受临床评估。据我们所知，没有螯合剂 - 抗体或螯合剂 - 微胞体结合物，或者使用临床上可以在房间快速用ZR-89（PET成像）和LU-177（TRT）标记温度。基于二肽尿素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，类似物（例如 LU-177-PSMA-617和AC-225-PSMA-617在患者中显示出明显的疗效。然而，用LU-177-PSMA-617治疗的患者经常复发，并用AC-225-PSMA-挽救治疗 617虽然有效，但由于唾液腺毒性而受到限制。使用放射标记的抗体具有被证明可以避免唾液腺定位，但可能导致骨髓抑制抗体的生物半衰期更长。 ZR-89-DFO-EAB2M MINIBODY是在I期临床研究中进行了评估，发现表现出低唾液腺定位，而表现出比相应的ZR-89-DFO-J591短得多的生物半衰期抗体结合物。 SBIR I期项目的拟议研究将开发合成并评估新型ZR-89，LU-177和TH-227的性能前列腺特异性膜抗原（PSMA）完整的小体构建体，利用单个螯合剂适用于所有三个辐射仪，用于病变检测，治疗和监测患者对放射性核素治疗的反应。这些研究将使在第二阶段的发展靶向正电子，β粒子和α粒子辐射的第一个疗法剂到PSMA 表达肿瘤。