Abstract
Purpose :
HPV-derived Virus Like Particles (VLPs) have been previously described to have the ability to selectively target a large panel of solid tumor types by binding to specifically modified heparan sulphate proteoglycans (HSPGs) on the tumor cell surface. The investigational VDC, belzupacap sarotalocan (AU-011), is composed of a modified VLP conjugated to a novel photosensitizer and is currently in phase 2 clinical trials for the treatment of primary choroidal melanoma. Upon light activation, AU-011 causes membrane disruption leading to acute cellular necrosis, tumor regression and an anti-tumor immune response in murine tumor models. With the ability to target a broad range of tumor types, AU-011 has the potential to treat tumors that metastasize to the choroid using the same treatment paradigm. We have previously shown anti-tumor activity of AU-011 in mouse models of breast and lung cancer. The purpose of this study was to expand to other cancer types that metastasize to the choroid as well as to explore the dose response.
Methods :
In vitro efficacy was evaluated in a panel of cancer cell lines. Cells were treated with AU-011, and cell binding and cell killing were evaluated by flow cytometry. HSPG targeting was assessed by inhibiting HSPGs binding with exogenous heparin. In vivo efficacy was evaluated by utilizing EMT6 (breast), CT26 (colon) and RENCA (renal) syngeneic mouse models. Subcutaneous tumors were treated when they reached a size of ~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 all cancer cell lines tested, the in vitro cell binding and cell killing potency were under 100pM. 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 dose dependent activity and delay of tumor growth in EMT6, CT26, and RENCA murine tumor models.
Conclusions :
These data demonstrate that AU-011 can bind to, and kill, cells derived from cancer types known to metastasize to the choroid. Furthermore, AU-011 showed dose dependent activity in vivo using cognate tumor models. The studies herein support further development of AU-011 for choroidal metastasis.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.