PO.ET08.03 · 实验与分子治疗
靶向CAIX的新型肽类放射性配体在透明细胞肾细胞癌（ccRCC）中的诊疗一体化应用
Novel peptide radioligands targeting CAIX for theranostic applications in clear cell renal cell carcinoma (ccRCC)
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
碳酸酐酶IX（CAIX）是一种缺氧诱导型跨膜酶，在透明细胞肾细胞癌（ccRCC）及其他多种实体瘤中高表达，使其成为放射诊疗一体化开发的一个有吸引力的靶点。利用PepLib的肽发现与优化平台，我们鉴定出一种单环肽配体4B043（19个氨基酸，一个二硫键），它是一种高亲和力的CAIX结合物。4B043对人CAIX表现出亚纳摩尔级的亲和力（KD≈86 pM），并对犬、小鼠和食蟹猴的CAIX具有强烈的跨物种结合。在荷VMRC-RCW肿瘤模型的Balb/c裸鼠中，⁶⁸Ga-4B043在注射后4小时显示出高肿瘤摄取（约55 %ID/g），肿瘤与肾脏（T/K）比值≈0.5。经结构优化后，⁶⁸Ga-2B002在保持高肿瘤摄取的同时，显著降低了肾脏蓄积（4小时T/K≈2）。受这些临床前数据的鼓舞，⁶⁸Ga-4B043被推进至一项人体研究者发起的临床试验（IIT）。在ccRCC患者中，⁶⁸Ga-4B043在肾肿瘤病灶中表现出高摄取。由于CAIX在正常胃和小肠组织中表达，⁶⁸Ga-4B043在患者的这些器官中也显示出显著摄取。值得注意的是，患者的肾脏摄取极低，2小时时肿瘤与肾脏比值>8，这与CDX模型形成鲜明对比。4B043及其优化衍生物2B002代表了一类新型CAIX靶向肽类放射性配体，具有优异的肿瘤摄取、良好的生物分布和可观的转化潜力。这些数据支持将它们进一步开发为诊疗一体化药物，用于CAIX表达肿瘤（包括ccRCC）的成像和靶向放射性配体治疗。
查看英文原文 English abstract
Carbonic anhydrase IX (CAIX) is a hypoxia-inducible transmembrane enzyme highly expressed in clear cell renal cell carcinoma (ccRCC) and several other solid tumors, making it an attractive target for radiotheranostic development.Using PepLib's peptide discovery and optimization platform, we identified a monocyclic peptide ligand, 4B043 (19 amino acids, one disulfide bond) as a high-affinity CAIX binder. 4B043 exhibited sub-nanomolar affinity to human CAIX (K D ≈ 86 pM) and strong cross-species binding to canine, mouse, and cynomolgus monkey CAIX. In Balb/c nude mice bearing VMRC-RCW tumor models, ⁶⁸Ga-4B043 showed high tumor uptake (~55 %ID/g) with a tumor-to-kidney (T/K) ratio ≈ 0.5 at 4 h post-injection. After structural optimization, ⁶⁸Ga-2B002 maintained high tumor uptake while significantly reducing kidney accumulation (T/K ≈ 2 at 4 h). Encouraged by these preclinical data, ⁶⁸Ga-4B043 was advanced into a human IIT. In ccRCC patients, ⁶⁸Ga-4B043 demonstrated high uptake in renal tumor lesions. Due to CAXI expression in normal gastric and small intestinal tissues, ⁶⁸Ga‑4B043 also showed notable uptake in these organs in patients. Notably, kidney uptake was remarkably low in patients, with a tumor-to-kidney ratio > 8 at 2 h, in clear contrast to the CDX model.4B043 and its optimized derivative 2B002 represent a novel class of CAIX-targeted peptide radioligands with excellent tumor uptake, favorable biodistribution, and promising translational potential. These data support their further development as theranostic agents for imaging and targeted radioligand therapy in CAIX-expressing tumors, including ccRCC.
利益披露 Disclosure
W. Xu, None..
J. Zhang, None.