Development of At-211-Labeled Reagents for Therapy of Metastatic Prostate Cancer

用于治疗转移性前列腺癌的 At-211 标记试剂的开发

基本信息

批准号：
8657828
负责人：
DANIEL SCOTT WILBUR
金额：
$ 23.66万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8657828
关键词：
Address Affinity Animals Antibodies Astatine Binding Biological Models Blood Blood Chemical Analysis Body Weight Bombesin Bombesin Antagonist Bombesin Receptor Boron Cancer Patient Carbon Cell Line Cells Charge Coupling Data Development Disease Distant Metastasis Drug Kinetics Drug or chemical Tissue Distribution Enzymes Evaluation Fab Immunoglobulins Filtration Funding Glutamate Carboxypeptidase II Goals Human Implant In Vitro Injection of therapeutic agent Kidney Label Liver Malignant Neoplasms Malignant neoplasm of prostate Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Metastatic to Modeling Mus New Agents Organ PC3 cell line Peptides Polyethylene Glycols Property Proteins Radioactivity Radioisotopes Reagent Recombinants Research SCID Mice Serum Albumin Streptavidin Survival Rate System Tissues Toxic effect Xenograft procedure base bone cytotoxic effective therapy immunogenicity improved in vivo inhibitor/antagonist killings molecular size mouse model prostate cancer cell prostate cancer model public health relevance receptor binding research study small molecule tibia tumor

项目摘要

DESCRIPTION (provided by applicant): In the proposed studies, new 211At-labeled reagents will be developed for application to therapy of metastatic prostate cancer. The new reagents will target the prostate specific membrane antigens (PSMA) or gastrin-releasing peptide receptors (GRP-R) on human prostate cancer cells. The studies will evaluate the in vitro binding and internalization of the new agents in C4-2 and PC-3 human prostate cancer cells. The studies will also evaluate tumor localization, pharmacokinetics and tissue distributions in SCID mice bearing C4-2 human prostate cancer xenografts, and evaluate the efficacy and toxicity of the best candidates in a "quasi"-metastatic bone metastases model in SCID mice. Targeting of the prostate cancer cells will be achieved by using an anti-PSMA antibody Fab4, the GRP-R-binding peptide bombesin, or a high binding affinity inhibitor of the enzymatic activity of PSMA. Because all three of these agents suffer from localization in kidney, protein-based conjugates will be prepared that have physical sizes and charges that exclude them from that organ. In specific aim 1 (SA 1), the antibody Fab4 fragment will be conjugated with four molecules of differing size and charge that contain the decaborate(2-) and branched-chain discrete-sized polyethyleneglycol (dPEG) moieties. In specific aim 2, bombesin or a PSMA inhibitor will be combined with decaborate(2-) in a trifunctional reagent. Those trifunctional molecules will be conjugated with recombinant streptavidin (rSAv) and that conjugate will be succinylated to demonstrate cancer targeting in that model system. In specific aim 3, the same molecules used in SA1 and SA2 will be conjugated with recombinant human serum albumin (rHSA) to provide 211At-labeled reagents that will be excluded from kidney, but will also have low immunogenicity. In specific aim 4, the three 211At-labeled reagents from SA1-3 that have the most favorable properties will be evaluated for efficacy and toxicity in a SCID mouse model for prostate cancer metastatic to bone. From the research effort one or two new 211At-containing reagents will be identified as having promise for more extensive evaluation in treatment of metastatic prostate cancer.

描述（由申请人提供）：在拟议的研究中，将开发新的211At标记试剂用于治疗转移性前列腺癌。新试剂将针对人类前列腺癌细胞上的前列腺特异性膜抗原（PSMA）或胃泌素释放肽受体（GRP-R）。这些研究将评估新药物在 C4-2 和 PC-3 人类前列腺癌细胞中的体外结合和内化。这些研究还将评估携带 C4-2 人类前列腺癌异种移植物的 SCID 小鼠的肿瘤定位、药代动力学和组织分布，并评估最佳候选药物在 SCID 小鼠“准”转移性骨转移模型中的功效和毒性。通过使用抗 PSMA 抗体 Fab4、GRP-R 结合肽铃蟾肽或 PSMA 酶活性的高结合亲和力抑制剂，可以实现前列腺癌细胞的靶向。由于所有这三种药物都在肾脏中定位，因此将制备基于蛋白质的缀合物，其物理尺寸和电荷将它们排除在该器官之外。在特定目标 1 (SA 1) 中，抗体 Fab4 片段将与四个不同大小和电荷的分子缀合，其中包含十硼酸 (2-) 和支链离散大小的聚乙二醇 (dPEG) 部分。在具体目标 2 中，铃蟾肽或 PSMA 抑制剂将与三功能试剂中的十硼酸盐 (2-) 结合。这些三功能分子将与重组链霉亲和素 (rSAv) 结合，并且该结合物将被琥珀酰化，以证明该模型系统中的癌症靶向作用。在具体目标3中，SA1和SA2中使用的相同分子将与重组人血清白蛋白（rHSA）缀合，以提供211At标记的试剂，该试剂将被排除在肾脏之外，但也具有低免疫原性。在具体目标 4 中，来自 SA1-3 的三种具有最有利特性的 211At 标记试剂将在 SCID 小鼠模型中评估前列腺癌骨转移的功效和毒性。通过研究工作，将鉴定出一两种新的含 211At 试剂，有望对转移性前列腺癌的治疗进行更广泛的评估。