The work outlined herein describes AU-011, a novel recombinant papillomavirus-like particle (VLP) drug conjugate and its initial evaluation as a potential treatment for primary uveal melanoma. The VLP is conjugated with a phthalocyanine photosensitizer, IRDye 700DX, that exerts its cytotoxic effect through photoactivation with a near-infrared laser. We assessed the anticancer properties of AU-011 in vitro utilizing a panel of human cancer cell lines and in vivo using murine subcutaneous and rabbit orthotopic xenograft models of uveal melanoma. The specificity of VLP binding (tumor targeting), mediated through cell surface heparan sulfate proteoglycans (HSPG), was assessed using HSPG-deficient cells and by inclusion of heparin in in vitro studies. Our results provide evidence of potent and selective anticancer activity, both in vitro and in vivo. AU-011 activity was blocked by inhibiting its association with HSPG using heparin and using cells lacking surface HSPG, indicating that the tumor tropism of the VLP was not affected by dye conjugation and cell association is critical for AU-011–mediated cytotoxicity. Using the uveal melanoma xenograft models, we observed tumor uptake following intravenous (murine) and intravitreal (rabbit) administration and, after photoactivation, potent dose-dependent tumor responses. Furthermore, in the rabbit orthotopic model, which closely models uveal melanoma as it presents in the clinic, tumor treatment spared the retina and adjacent ocular structures. Our results support further clinical development of this novel therapeutic modality that might transform visual outcomes and provide a targeted therapy for the early-stage treatment of patients with this rare and life-threatening disease. Mol Cancer Ther; 17(2); 565–74. ©2017 AACR.

中文翻译：

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一种用于治疗原发性葡萄膜黑色素瘤的红外染料偶联病毒样颗粒

本文概述的工作描述了 AU-011，一种新型重组乳头瘤病毒样颗粒 (VLP) 药物偶联物及其作为原发性葡萄膜黑色素瘤潜在治疗方法的初步评估。VLP 与酞菁光敏剂 IRDye 700DX 结合，通过近红外激光的光活化发挥其细胞毒性作用。我们使用一组人类癌细胞系在体外评估了 AU-011 的抗癌特性，并使用葡萄膜黑色素瘤的鼠皮下和兔原位异种移植模型在体内评估了 AU-011 的抗癌特性。通过细胞表面硫酸乙酰肝素蛋白聚糖 (HSPG) 介导的 VLP 结合（肿瘤靶向）的特异性使用 HSPG 缺陷细胞并通过在体外研究中加入肝素进行评估。我们的结果提供了体外和体内有效和选择性抗癌活性的证据。AU-011 活性通过使用肝素和使用缺乏表面 HSPG 的细胞抑制其与 HSPG 的结合而被阻断，表明 VLP 的肿瘤趋向性不受染料缀合的影响，并且细胞结合对 AU-011 介导的细胞毒性至关重要。使用葡萄膜黑色素瘤异种移植模型，我们观察了静脉内（鼠类）和玻璃体内（兔）给药后的肿瘤吸收，以及在光活化后，有效的剂量依赖性肿瘤反应。此外，在兔原位模型中，它密切模拟了临床上出现的葡萄膜黑色素瘤，肿瘤治疗使视网膜和邻近的眼部结构免受伤害。我们的结果支持这种新型治疗方式的进一步临床开发，这种方式可能会改变视觉效果，并为患有这种罕见且危及生命的疾病的患者的早期治疗提供靶向治疗。摩尔癌症治疗; 17(2); 565-74。©2017 AACR。