Preparation and Evaluation of Radiolabeled Antibody Recruiting Small Molecules That Target Prostate-Specific Membrane Antigen for Combined Radiotherapy and Immunotherapy
Preparation and Evaluation of Radiolabeled Antibody Recruiting Small Molecules That Target Prostate-Specific Membrane Antigen for Combined Radiotherapy and Immunotherapy
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DOI：
10.1021/acs.jmedchem.5b01881
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发表时间：
2016-03-24
影响因子：
7.3
通讯作者：
Valliant, John F.
中科院分区：
文献类型：
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作者：
Genady, Afaf R.;Janzen, Nancy;Valliant, John F.
确定了开发一种单一药剂的可行性，该单一药剂可以提供放射性碘，并通过将内源性抗体作为抗体招募小分子（ARM）来指导细胞免疫功能。合成并在体外和体内筛选了新的前列腺特异性膜抗原 (PSMA) 结合配体文库，其中包含抗体招募 2,4-二硝基苯基 (DNP) 基团和碘。先导化合物 (9b) 显示出对 PSMA 的高亲和力以及结合抗 DNP 抗体的能力。碘 125 类似物的生物分布研究显示，注射后 1 小时，LNCaP 异种移植肿瘤中的 ID/g 为 3%，肿瘤与血液和肿瘤与肌肉的比例分别为 10:1 和 44:1。放射性标记的类似物被 LNCaP 细胞结合并内化，使用已知的 PSMA 抑制剂阻断这两种功能。第二个候选者表现出高肿瘤摄取（>10% ID/g），但与抗 DNP 抗体的结合最小。报道的化合物代表了专门为前列腺癌联合免疫疗法和放射疗法开发的小分子的第一个例子。
The feasibility of developing a single agent that can deliver radioactive iodine and also direct cellular immune function by engaging endogenous antibodies as an antibody-recruiting small molecule (ARM) was determined. A library of new prostate-specific membrane antigen (PSMA)-binding ligands that contained antibody-recruiting 2,4-dinitrophenyl (DNP) groups and iodine were synthesized and screened in vitro and in vivo. A lead compound (9b) showed high affinity for PSMA and the ability to bind anti-DNP antibodies. Biodistribution studies of the iodine-125 analogue showed 3% ID/g in LNCaP xenograft tumors at 1 h postinjection with tumor-to-blood and tumor-to-muscle ratios of 10:1 and 44:1, respectively. The radiolabeled analogue was bound and internalized by LNCaP cells, with both functions blocked using a known PSMA inhibitor. A second candidate showed high tumor uptake (>10% ID/g) but had minimal binding to anti-DNP antibodies. The compounds reported represent the first examples of small molecules developed specifically for combination immunotherapy and radiotherapy for prostate cancer.