Abstract
Purpose :
AU-011 is an investigational virus-like drug conjugate composed of a virus-like particle conjugated to a photosensitizer. AU-011 binds to tumor cells by selectively targeting specifically modified heparan sulphate proteoglycans (HSPGs) on the tumor cell surface. Upon light activation, AU-011 is designed to cause membrane disruption leading to acute cellular necrosis and tumor regression in vivo. The HPV derived VLPs have a tumor tropic nature and have been previously described to have the ability to target a large panel of tumor types. As such, AU-011 has the potential to treat choroidal metastasis using the same treatment paradigm. The most common primary tumors known to metastasize to the choroid are breast and lung. The purpose of this study was to evaluate the potential to treat choroidal metastasis by evaluating the effect of AU-011 in these cancer types both in vitro and in vivo.
Methods :
In vitro efficacy was evaluated in a panel of human breast and lung cancer cell lines. Cells were treated with AU-011, and cell binding and cell killing were evaluated by flow cytometry. HSPG targeting and tumor specificity were assessed by inhibiting binding to HSPGs with exogenous heparin. In vivo efficacy was evaluated by utilizing 4T1 and EMT6 syngeneic mouse models for breast cancer. Tumor cells were implanted subcutaneously. AU-011 treatment was initiated when tumors reached approximately 50 mm3. Treatment consisted of a single intravenous administration of AU-011 followed 12 hours later by external exposure to near-IR light. Tumor volumes were measured over time.
Results :
In both panels of cancer cell lines, the in vitro cell binding and cell killing potency were in the picomolar range (EC50: 17-250pM). Cell binding and subsequent AU-011 mediated cell death was inhibited by heparin, demonstrating that AU-011 can bind to these tumor cell types in an HSPG dependent manner. In vivo AU-011 treatment demonstrated activity and reduction of growth in 4T1 and EMT6 murine breast tumor models, further corroborating data previously obtained in other murine cancer models.
Conclusions :
These data demonstrated that AU-011 can bind to, and kill, cells derived from the most common cancer types known to metastasize to the choroid. Furthermore, AU-011 showed activity in vivo using cognate tumor models. The studies herein support further development of AU-011 for choroidal metastasis.
This is a 2021 ARVO Annual Meeting abstract.