Cross-reactivity to glutamate carboxypeptidase III causes undesired salivary gland and kidney uptake of PSMA-targeted small-molecule radionuclide therapeutics
Cross-reactivity to glutamate carboxypeptidase III causes undesired salivary gland and kidney uptake of PSMA-targeted small-molecule radionuclide therapeutics
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DOI：
10.1007/s00259-022-05982-8
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发表时间：
2022-10-03
影响因子：
9.1
通讯作者：
Bassi, Gabriele
中科院分区：
文献类型：
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作者：
Lucaroni, Laura;Georgiev, Tony;Bassi, Gabriele
目的最近，Pluvicto（TM）（[Lu-177]Lu-PSMA-617），一种小分子前列腺特异性膜抗原（PSMA）放射性配体治疗剂，已被FDA批准用于转移性去势抵抗性前列腺癌。Pluvicto（TM）和其他PSMA靶向放射性配体治疗剂（RLT）由于在某些健康组织（如唾液腺和肾脏）中的积累而显示出副作用。到目前为止，尚未阐明PSMA靶向RLT的不期望积累的分子机制。方法将PSMA序列与整个人类蛋白质组进行比较，以确定与靶点密切相关的蛋白质。我们已经确定谷氨酸羧肽酶III（GCPIII），N-乙酰化α-连接的酸性二肽酶样1（NAALADL-1），和转铁蛋白受体1（TfR 1）的细胞外目标与PSMA的最高相似性。通过荧光偏振测量化合物1对PSMA、GCPIII、NAALADL-1和TfR 1的亲和力。使用市售抗体，通过对人唾液腺和肾脏的免疫荧光来评估推定的抗靶标GCPIII的表达。结果在荧光偏振实验中，Pluvicto（TM）的荧光衍生物（化合物1）与PSMA和GCPIII紧密结合，而与NAALADL-1和TfR 1没有观察到相互作用。免疫荧光分析显示GCPIII在健康人肾脏和唾液腺中均有大量表达。结论GCPIII在肾脏和唾液腺中的膜表达可能是Pluvicto（TM）和其他Glu-ureido PSMA放射性药物在患者体内蓄积的根本原因。
Purpose Recently, Pluvicto (TM) ([Lu-177]Lu-PSMA-617), a small-molecule prostate-specific membrane antigen (PSMA) radioligand therapeutic, has been approved by the FDA in metastatic castration-resistant prostate cancer. Pluvicto (TM) and other PSMA-targeting radioligand therapeutics (RLTs) have shown side effects due to accumulation in certain healthy tissues, such as salivary glands and kidney. Until now, the molecular mechanism underlying the undesired accumulation of PSMA-targeting RLTs had not been elucidated. Methods We compared the sequence of PSMA with the entire human proteome to identify proteins closely related to the target. We have identified glutamate carboxypeptidase III (GCPIII), N-acetylated alpha-linked acidic dipeptidase like 1 (NAALADL-1), and transferrin receptor 1 (TfR1) as extracellular targets with the highest similarity to PSMA. The affinity of compound 1 for PSMA, GCPIII, NAALADL-1, and TfR1 was measured by fluorescence polarization. The expression of the putative anti-target GCPIII was assessed by immunofluorescence on human salivary glands and kidney, using commercially available antibodies. Results A fluorescent derivative of Pluvicto (TM) (compound 1) bound tightly to PSMA and to GCPIII in fluorescence polarization experiments, while no interaction was observed with NAALADL-1 and TfR1. Immunofluorescence analysis revealed abundant expression of GCPIII both in healthy human kidney and salivary glands. Conclusion We conclude that the membranous expression of GCPIII in kidney and salivary gland may be the underlying cause for unwanted accumulation of Pluvicto (TM) and other Glu-ureido PSMA radio pharmaceuticals in patients.