Abstract P3045: The ELP-VEGF Fusion Protein Is Bioavailable After Subcutaneous Administration And Prevents Increased Blood Pressure In Response To Placental Ischemia

Abstract

Preeclampsia is often characterized by high circulating levels of sFlt-1 and low VEGF and PlGF. VEGF supplementation therapy has shown promise in preclinical models, however rapid plasma clearance hampers the use of VEGF as a therapeutic. We fused human VEGF-A 121 with the Elastin-like Polypeptide (ELP) protein carrier. The objective of this study was to test the pharmacokinetics and therapeutic efficacy of ELP-VEGF when given via intravenous (IV) and subcutaneous (SC) administration routes.Fluorescently labeled ELP-VEGF was administered via daily IV (5 mg/kg/day) or SC injection (50 mg/kg/day). Plasma levels were determined by direct fluorescence measurement, and whole-body fluorescence imaging was used to determine total tissue clearance rates. The ability of SC delivered ELP-VEGF to modulate blood pressure was tested in a rat model of placental ischemia.When administered via IV injection, ELP-VEGF cleared from the plasma with an average daily half-life of 2.17±1.14 h. SC injected ELP-VEGF was absorbed into the blood and peaked within 2 hours of each injection. Tissue levels peaked 2h after each injection and remained elevated prior to the next injection, resulting in accumulation and high whole-body bioavailability. In pregnant rats, placental ischemia induced an increase in mean arterial pressure (108 ±11 vs. 122±13 mmHg, p=0.024). Daily SC injection of ELP-VEGF (50 mg/kg/day) completely prevented placental ischemia-induced increases in blood pressure (107±11 vs. 109±9 mmHg, p=ns). These results demonstrate that ELP-VEGF is bioavailable via clinically relevant administration routes and is a promising candidate agent for preeclampsia therapy.