Abstract
Purpose :
AU-011 is a highly tumor targeted treatment for ocular melanoma which selectively binds to specifically modified heparan sulphate proteoglycans that are upregulated in tumors. AU-011 has been shown to work by a dual mechanism: Upon light activation, it causes acute cellular necrosis, membrane disruption and triggers an immunogenic cell death by releasing damage-associated-molecular-patterns.
AU-011 is currently in a Phase 1b/2 clinical trial for primary choroidal melanoma delivered by intravitreal injection followed by photoactivation 6-8 hours later.
Suprachoroidal injection is currently being evaluated in nonclinical studies with the goal to move into the clinic. Suprachoroidal delivery of AU-011 has the potential for better bioavailability in the tumor which may decrease the dose needed, increase the size range of tumors treated and could result in a better benefit/risk profile.
Methods :
VLP*Alexa488 with similar physical and chemical characteristics as AU-011 was administered in New Zealand White (NZW) rabbits by suprachoroidal injection at different volumes. Using optical coherence tomography (OCT) and fundus autofluorescence (FAF), ocular distribution was followed over time.
Anti-tumor effect of AU-011 was assessed in a NZW rabbit model of ocular melanoma. Human melanoma 92.1 cells were implanted in the choroid. AU-011 was administered by suprachoroidal injection followed by photoactivation once a week for three consecutive weeks. Tumors were evaluated by histopathology.
Results :
AU-011 distributed in the choroid in a volume-dependent fashion within 30 minutes. AU-011 was not cleared from the choroid for several days. At 100μl AU-011 was distributed to approximately 75% of the posterior globe. Imaged by OCT, a fluid bleb was observed in the suprachoroidal space 30 minutes post-injection, which returned to normal by 24 hours.
Efficacy was established in a rabbit model of ocular melanoma. Tumor regression was seen in all rabbits after suprachoroidal administration of 100 ug AU-011 and there was evidence of tumor responses by histological evaluation, characterized by cancer cell necrosis and an inflammatory infiltrate.
Conclusions :
These data support further development of suprachoroidal injection of AU-011 showing excellent distribution in the suprachoroidal space over an extended amount of time which resulted in potent anti-cancer activity in a preclinical model of choroidal melanoma.
This is a 2020 ARVO Annual Meeting abstract.