Innovative Antibodies to treat Cardiovascular Disease
Cardiovascular disease (CVD) is presently a leading cause of death and its impact is even increasing due to CVD complications in surviving oncology (cardio-oncology) and HIV patients. Current treatments are focused on lowering plasma cholesterol levels traditionally through statins and more recently through PCSK9 inhibitors. However, approximately 60% of patients treated with the classic treatment, with on-target plasma cholesterol levels are still suffering acute ischemic events (ACS) due to the silent internalization of cholesterol in their coronary arteries.
Cellular cholesterol internalization is a critical currently untreated step. That is why patients with low plasma cholesterol levels suffer ACS episodes. The cellular internalization of cholesterol has to be interrupted. In this scenario, we have developed antibodies that efficiently and specifically treat the entrapment of cholesterol in vasculature and heart.
The group of Dra Llorente identified a critical receptor, low-density lipoprotein receptor (LRP1) that is key for intracellular entrapment of colesterol. LRP1 is strongly upregulated in coronary arteries and myocardium of patients exposed to prevalent cardiovascular factors. In this receptor we have identified the epitope (P3) and the specific aminoacidic sequence in charge of cholesterol internalization. Anti-P3 antibodies, developed by SCAC, scientific and technical service of the UAB, specifically interrupt the interaction of the receptor with atherogenic lipoproteins without altering other essential functions of the receptor.
In the article, we demonstrate that P3 immunization raised anti-P3 antibodies that are therapeutically efficient in atherosclerosis. Anti-P3 antibodies block cholesterol accumulation in vascular cells and counteract high-fat diet induced atherosclerosis in rabbits. The therapeutic effect was evidenced by molecular and immunohistochemical studies and, importantly, by non-invasive clinical methods including 18F-FDG PET/CT and Doppler Ultrasound Ecography showing a reduction in the standardized uptake value (SUV) and in the resistive index (RI), imaging read-outs currently used for atherosclerosis diagnosis in humans.
Institute of Biomedical Research of Barcelona (IIBB). Spanish National Research Council (CSIC).
Lipids and Cardiovascular Pathology. Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau. Barcelona. Spain.
CIBER enfermedades cardiovasculares (CIBERcv).
Bornachea O, Benitez-Amaro A, Vea A, Nasarre L, de Gonzalo-Calvo D, Escola-Gil JC, Cedo L, Iborra A, Martínez-Martínez L, Juarez C, Camara JA, Espinet C, Borrell-Pages M, Badimon L, Castell J, Llorente-Cortés V. Immunization with the Gly(1127)-Cys(1140) amino acid sequence of the LRP1 receptor reduces atherosclerosis in rabbits. Molecular, immunohistochemical and nuclear imaging studies. Theranostics. 2020 Feb 10;10(7):3263-3280. doi: 10.7150/thno.37305. eCollection 2020. PubMed PMID: 32194867; PubMed Central PMCID: PMC7053206