Abstract

Purpose

Pluvicto™ ([¹⁷⁷Lu]Lu-PSMA-617), a radioligand therapeutic targeting prostate-specific membrane antigen (PSMA), has been recently approved for the treatment of metastatic castration-resistant prostate cancer (mCRPR). The drug suffers from salivary gland and kidney uptake that prevents its dose escalation to potentially curative doses. In this work, we sought to potentiate the in vivo anti-cancer activity of Pluvicto™ by combining it with L19-IL2, a clinical-stage investigational medicinal product based on tumor-targeted interleukin-2.

Methods

We established a new PSMA-expressing model (HT-1080.hPSMA) and validated it using a fluoresceine analogue of PSMA-617 (compound 1). The HT-1080.hPSMA model was used to study the saturation and tumor retention of Pluvicto™ (compound 2) and to run combination therapy studies with L19-IL2. To complement our understanding of the mechanism of action of this novel combination, we conducted proteomics experiments on tumor samples after therapy with Pluvicto™ alone or in combination with the immunocytokine.

Results

High, selective, and long-lived tumor uptake was observed for Pluvicto™ (2) in the novel HT-1080.hPSMA model. Therapy studies in HT-1080.hPSMA tumor-bearing mice revealed that the combination of Pluvicto™ (2) plus L19-IL2 mediated curative and durable responses in all animals. Potent in vivo anti-cancer activity was observed solely for the combination modality, at doses that were well tolerated by treated animals. Proteomics studies indicated that L19-IL2 boosts the activation of the immune system in animals pre-treated with Pluvicto™.

Conclusion

The therapeutic efficacy of Pluvicto™ at low radioactive doses can be effectively enhanced by the combination with L19-IL2. Our findings warrant further clinical exploration of this novel combination modality.

中文翻译：

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靶向白细胞介素 2 增强 Pluvicto™ 的体内抗癌活性

摘要

目的

Pluvicto™ ([ ¹⁷⁷ Lu]Lu-PSMA-617) 是一种靶向前列腺特异性膜抗原 (PSMA) 的放射性配体治疗剂，最近已被批准用于治疗转移性去势抵抗性前列腺癌 (mCRPR)。该药物会受到唾液腺和肾脏的吸收，从而阻止其剂量增加到潜在的治疗剂量。在这项工作中，我们试图通过将 Pluvicto™ 与 L19-IL2 结合来增强 Pluvicto™ 的体内抗癌活性，L19-IL2 是一种基于肿瘤靶向白细胞介素 2 的临床阶段研究药物产品。

方法

我们建立了一个新的 PSMA 表达模型 (HT-1080.hPSMA)，并使用 PSMA-617（化合物 1）的荧光素类似物对其进行了验证。 HT-1080.hPSMA 模型用于研究 Pluvicto™（化合物 2）的饱和度和肿瘤保留，并与 L19-IL2 进行联合治疗研究。为了补充我们对这种新型组合的作用机制的理解，我们对单独使用 Pluvicto™ 或与免疫细胞因子联合治疗后的肿瘤样本进行了蛋白质组学实验。

结果

在新型 HT-1080.hPSMA 模型中观察到 Pluvicto™ (2) 具有高、选择性和长寿命的肿瘤摄取。对 HT-1080.hPSMA 荷瘤小鼠的治疗研究表明，Pluvicto™ (2) 与 L19-IL2 的组合可在所有动物中介导治愈性和持久的反应。仅在组合方式中观察到有效的体内抗癌活性，且剂量被治疗的动物良好耐受。蛋白质组学研究表明，L19-IL2 可增强经 Pluvicto™ 预处理的动物免疫系统的激活。

结论

与L19-IL2联用可有效增强Pluvicto™在低放射性剂量下的治疗效果。我们的研究结果值得对这种新型组合方式进行进一步的临床探索。