PRL3, a novel therapeutic target in neovascular eye diseases

Abstract

Purpose : There is an urgent need to discover new therapeutic targets for the treatment of wet AMD and DME patients who are resistant to anti-VEGF therapy. Phosphatase of Regenerating Liver-3 (PRL3) is an oncotarget expressed in multiple cancers but not in healthy human tissues. PRL3-zumab, a first-in-class humanized anti-PRL3 monoclonal antibody, has passed Phase I clinical trials and is in multinational Phase II trials for solid tumors. As PRL3 plays a role in tumor angiogenesis, we hypothesize that PRL3 is involved in neovascular eye diseases and PRL3-zumab could be used to treat these diseases.

Methods : Choroid tissues (n=33) from CNV mouse model and retina tissues (n=14) from OIR mouse model were analyzed for PRL3 protein expression by western blotting. In vivo treatment using mouse anti-PRL3 antibody via IVT or IV route was done in CNV model to assess therapeutic efficacy. In vitro studies using Human Retina Microvascular Endothelial Cells (HRMECs) were conducted to assess the effect of PRL3 overexpression on VEGF signaling and endothelial proliferation, migration and permeability of monolayer. The safety profile of PRL3-zumab was validated using NZW rabbit (IVT, n=9) and Cynomolgus monkey models (IV, n=40).

Results : PRL3 was specifically overexpressed in choroid tissues (CNV model) and retina tissues (OIR model). Anti-PRL3 antibody treatment reduced vascular leakage in CNV lesions. IV of the antibody showed significantly better (86%, p=0.003) efficacy compared to IVT route due to a greater dose permitted by IV. VEGF treatment on HRMECs upregulated endothelial PRL3 protein. Overexpressing PRL3 in HRMECs via retroviral transduction enhanced proliferation (p=0.018), migration (p=0.043) and permeability (p=0.0499) of monolayer. Endothelial PRL3 overexpression had a significant downstream effect on VEGF signaling: Increased pSrc (p=0.038), pAkt (p=0.04), pERK1/2 (p=0.02) and pPaxillin (p=0.039) and decreased VE-Cadherin (p=0.0028), ZO-1 (p=0.032) and VEGFR2 (p=0.0001). Ocular and systemic safety of PRL3-zumab (IVT and IV) have been well validated.

Conclusions : Our results have demonstrated specific PRL3 overexpression in mouse choroid and retina tissues with pathological angiogenesis, and PRL3 is an independent driver of ocular angiogenesis. IV regime of anti-PRL3 antibody is a safe and viable option with better efficacy. The strong safety profile of PRL3-zumab (IVT and IV) supports drug repurposing efforts in neovascular eye diseases.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.