LPCBioMab, Antibody-Functionalized Lipoprotein Complexes (LPC) including ApoA1 and a macrophage-repolarizing drug for the targeted therapy of atherosclerosis – LCPBioMab

The LPCBioMab project wants to develop a targeted therapy of atherosclerosis associated with a companion diagnostic tool. We aim to engineer biomimetic, biocompatible ApoA1-based lipoprotein complexes (LPC) inspired by nature, containing a natural compound for metabolic regulation of intimal macrophages (IMs) and functionalized with two types of human or humanized antibodies (HuAbs) targeting lesional IMs and oxidized apolipoprotein A1. ApoA1, the major protein of high-density lipoprotein (HDL) particles, is essential for several atheroprotective activities, including cellular cholesterol efflux and the control of inflammatory response, of platelet activation and of cell death. However, it is known that the inflammatory and oxidative microenvironment of atheromatous plaques leads to the formation of dysfunctional oxidized ApoA1 (oxApoA1). The envisaged lipoprotein complexes will combine unprecedented added advantages: (1) the inclusion of a recombinant native ApoA1 or a ApoA1 variant (associated with resistance to cardiovascular diseases) to replenish the stock of ApoA1 proteins that have been oxidized in inflammatory plaques; (2) a double targeting (oxApoA1 and IM) of the atheroma using proprietary HuAbs; (3) the loading within LPC of a fatty acid, the conjugated linoleic acid (CLA) that will display repolarizing properties towards the macrophage immunoregulatory phenotype. Because of their preponderant role in the pathogenesis, IMs represent an ideal target for therapy. They can transform into foamy macrophages (FM) after phagocytosis of oxidized low-density lipoproteins (oxLDL). FMs progressively become unable to sustain cholesterol efflux and efferocytosis, promoting the progression of the prothrombotic necrotic core toward rupture. Besides FMs, IMs in atherosclerotic lesions have long been known to be heterogeneous phenotypically and functionally, moving along a continuum from inflammatory (inflMP) to immunoregulatory (regMP) macrophages. Non-foamy InflMP present in this vulnerable area were also described to play a role in plaque progression towards rupture. Besides immunoregulation, CLA will dampen FM formation by inhibiting oxLDL uptake and inducing ATP-binding cassette transporter A1-(ABCA1) and ABCG1 receptors. Increasing the non-oxidized ApoA1 level might also induce the anti-inflammatory phenotype of lesional macrophages. The objective of LPCBioMab is therefore to design and produce an original one-in-all ApoA1/CLA therapeutic approach to counter both the atherogenic FM and the neighboring inflMP. In parallel, pitavastatin will be loaded in LPC and used as reference for its anti-inflammatory action. The companion diagnostic LPC developed to monitor the therapy will be loaded with an iron-platinum alloy for Magnetic Resonance Imaging (MRI) detection to reduce the nanoparticle size while retaining high sensitivity. The targeting properties and expected atheroprotective effects will be evaluated in the apolipoprotein E-deficient (Apoe-/-) small animal model of atherosclerosis. If successful, the LPCBioMab project will be favorably positioned within the actual demand of new targeted therapeutic nano-objects to act on inflammation and immune system, which both play a key role in many disorders. In envisaged translational approaches, companion diagnosis tools will be proposed using the same HuAbs labelled with radiotracers for nuclear imaging.