An Infrared Dye-Conjugated Virus-like Particle for the Treatment of Primary Uveal Melanoma

• Type of Material: Article
• Authors: Rhonda C. Kines, Aura Biosciences; Isabella Varsavsky, Aura Biosciences; Sanghamitra Choudhary, Aura Biosciences; Debaditya Bhattacharya, Aura Biosciences; Sean Spring, Aura Biosciences; Roger McLaughlin, Aura Biosciences; Shin Kang, Emory University; Hans Grossniklaus, Emory University; Demetrios Vavvas, Harvard University; Stephen Monks, Aura Biosciences; John R. MacDougall, Aura Biosciences; Elisabet de los Pinos, Aura Biosciences; John T. Schiller, NCI
• Language: English
• Date: 2018-02-01
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©2017 American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158/1535-7163.MCT-17-0953
• Title of Journal or Parent Work: Molecular Cancer Therapeutics
• Volume: 17
• Issue: 2
• Start Page: 565
• End Page: 574
• Grant/Funding Information: All research was funded by Aura Biosciences.
• Keywords: Infection; Mutants; Life Sciences & Biomedicine; Papillomavirus Infections; Oncology; Animal model; I-125 Brachytherapy; Heparan sulfate; Choroidal melanoma; Expression; Science & Technology; Complications; Collaborative ocular melanoma
• Research Categories: Health Sciences, Opthamology; Health Sciences, Medicine and Surgery; Health Sciences, Oncology

Abstract

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.