314. Maternally sequestered biologics for treatment of preeclampsia

Abstract

Introduction Preeclampsia is a hypertensive syndrome of pregnancy with few pharmacological treatment options. The risk of for adverse fetal effects is a major limitation for drug development. Our lab has developed a protein-based drug carrier called elastin-like polypeptide (ELP) that is capable of stabilizing therapeutic proteins or peptides in the maternal circulation while preventing their placental transfer. Objective/Hypothesis We hypothesize that ELP can be optimized for maternally sequestered drug delivery by altering the polymer length. We further hypothesize that ELP can be fused to vascular endothelial growth factor (VEGF) to restore angiogenic balance while preventing fetal exposure to the therapeutic. Methods A library of ELP carriers ranging in size from 25 to 110 kDa was created. The pharmacokinetics, biodistribution, and placental transfer of each agent were determined in a rat pregnancy model. A 60 kDa ELP domain was fused to human VEGF-A121, and the pharmacokinetics were determined following repeat dosing intravenous or subcutaneous administration. Results The plasma half-life of ELP was inversely related to its molecular weight. As the size of the molecule increased, the renal ELP deposition decreased and the placenta and other maternal organ levels increased. Within the placenta, ELP was localized broadly in the labyrinth and along the chorionic plate. No ELP crossed the placental barrier at any size tested. When fused to VEGF, daily IV dosing lead to a 2.1 +/- 1.1 h half-life after each injection. SC administration lead to an increase in plasma ELP-VEGF levels over the first three hours, followed by a slow clearance phase over 24 h that was accompanied by dispersal of the protein from the SC injection site. Discussion This work demonstrates the utility of ELP as a tunable, long-circulating, non-toxic, maternally sequestered drug carrier. The ELP-VEGF fusion protein has potential as a novel biologic for treatment of preeclampsia.