Uveal melanoma, also known as choroidal melanoma, belongs to a group of rare diseases in ocular oncology for which there are no approved drugs available at present. While being a rare disease, it is the most common primary intraocular cancer in adults. Uveal melanoma is aggressive and life-threatening cancer with up to 50% of patients dying of fatal liver metastasis after treatment with standard therapies. These include radiotherapy, which is associated with severe vision loss and other long-term complications such as glaucoma, cataracts, and radiation retinopathy. Alternative therapy is total surgical removal of the eye (enucleation). Therefore, there is a high unmet need for a new targeted therapy that could enable early, less invasive, vision-sparing treatment of uveal melanoma.
Novel phototherapy AU-011
AU-011 is a novel targeted photoactive agent for the first-line treatment of uveal melanoma. It was designed to achieve local disease control while preserving vision of the patients. AU-011 is composed of 2 recombinantly expressed papillomavirus capsid proteins self-assembled into virus-like particle that is conjugated to a photosensitizer IRDye700. Tumor targeting of AU-011 is mediated through attachment to modified heparan sulphate proteoglycans (HSPGs) expressed on the surface of cancer cells. Multivalency of AU-011 permits many simultaneous sites of interaction, promoting a strong interaction with tumor cells and delivery of hundreds of payload molecules at once.
AU-011 is cytotoxic only when photoactivated with an ophthalmic laser, sparing surrounding key eye structures from damages. Its novel dual mechanisms of action act directly on the tumor via membrane disruption of tumor cells and indirectly by activating T cells through release of neoantigens from the damaged tumor cells. The activation of antitumor immunity has the potential to possibly result in the long-term survival of the treated patients. This phototherapy is well-tolerated, convenient, and a cost-effective treatment that can be given in an outpatient setting.
Preliminary investigation of AU-011
1. Efficacy and specificity of AU-011 upon photoactivation.
- Plate HSPG-expressing 92.1MEL uveal melanoma cells at a density of 2.5×10^4/500 µL in a 24-well plate and allow to grow for 48 hours.
- Incubate cells with defined amounts of IRDye 700DX, AU-011 alone or AU-011 with heparin for 1 hour.
- Illuminate cells with MLAKIT connected to ML6500 series laser (25 J/cm2, 689 nm). Acquire microscope images within 15 minutes after light treatment.
2. Influence of light exposure and AU-011 dose.
- Incubate uveal melanoma cells with AU-011 at four doses (300, 30, 3, 0 pm) for 1 hour at +4 ⁰C.
- Wash cells and illuminate with varying doses of 689 nm laser light (0, 6.25, 12.5, 25 or 50 J/cm2).
- Measure cell binding and cytotoxicity using LIVE/DEAD Yellow fixable stain and flow cytometry.
Only cells that were bound by AU-011 and exposed to laser light were noticeably affected by the treatment, becoming rounded and starting to detach (Fig. 1, circle). AU-011 activity was blocked by inhibiting its association with HSPG using soluble heparin, demonstrating the requirement of selective HSPG-binding for cell killing to occur. AU-011 was also found to have extremely strong tumor cell binding and potent cytotoxicity, which was directly proportional to the laser light dose (Fig. 2).
Figure 1. Rapid HSPG-mediated tumor cell killing by AU-011 upon activation by 25 J/cm2 Modulight laser at 689 nm. Click on the image to enlarge.
Figure 2. Influence of light exposure and AU-011 dose.
See the original related graphs & images in the referred publication.
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