Développement et validation de marqueurs et de traitements immunologiques innovants pour la caractérisation et la régression de la plaque d¿athérosclérose. – IMTAM

Atherosclerosis is an inflammatory disease characterized by intense immunological activity, which increasingly threatens human health worldwide

The aim of the current project is to develop novel immunological tools for improving the management of atherosclerotic patients.

The natural repertoire of Treg cells, which is responsible for the maintenance of immune homeostasis, also limits the development of atherosclerosis. Aterovax scientific founders demonstrated that subcutaneous delivery at sub-immunogenic concentrations of two peptides (p210 and p240) derived from ApoB-100, the major proteic component of the plaque, resulted not only in the prevention of plaque formation, but also in the arrest of progression of established plaques.

The objectives of this project are:
¿ To perform, in collaboration with a CRO, the studies required for the regulatory preclinical development of our most advanced candidates (p210 and p240).
¿ To further document the tolerogenic effect of our lead peptides p210 and p240.
¿ To perform optimized immune-profiling of experimental mouse models as well as of atherosclerosis patients.
¿ To search for new plaque epitotes, to serve as new peptide candidates.

At completion, this project should provide the data required for the preclinical file of Aterovax p210 and p240 leads, enabling Aterovax to initiate a phase I clinical trial to further develop one lead immuno-modulator peptide. This project should also generate new data and methods fo The main objective of the project is to develop a new immunotherapy for atherosclerosis.
Our approach is based on blocking atherosclerosis plaque inflammation through the stimulation of regulatory T (Treg) cells with rationally design peptides.
Recent studies identified a number of native and malondialdehyde (MDA)-modified peptide sequences in apolipoprotein (apo)B-100, the major protein component of low density lipoproteins (LDL), which induce immune responses in humans and reduce atherosclerosis in mice when administered with adjuvant.
An alternative way of modulating the immune response involves continuous subcutaneous infusion of low doses of antigen, which lead to the induction of a state of immune tolerance with significant dampening of pathogenic T cell responses. The feasibility of this novel strategy has already been demonstrated in mouse models.

The objective is then to move forward two candidate peptides (p210 and p240) through the preclinical path by optimizing efficacy models and preclinical and clinical end points, peptide design, peptide delivery and safety.

The current project associates the development of a new therapeutic approach to the characterization and the validation of new biomarkers (optimized immunoscope, TcLandscape).
These tools should optimize preclinical and clinical development by identifying early efficacy markers and allow high risk patient identification and stratification.
The consortium is composed of two biotech companies (Aterovax and TcLand Expression) and an academic laboratory (Cardiovascular Research Centre INSERM U689).

Aterovax will be involved in project coordination, preclinical development of p210 and p240 lead peptides and identification of new T epitopes of the plaque.

INSERM689 will be involved in further characterization of the mode of action and access to patient samples for epitotes and immunological signatures identification.

TcLand Expression will be involved in the identification of novel immunological signatures relevant for treatment efficacy and patients evaluation.

The ability of INSERM U689 to recruit patients and experimental samples and to perform high level fundamental research, combined with TcLand unique platform and technology and Aterovax expertise in preclinical development will make possible the identification and validation of innovative immuno-modulating peptides and biological markers.
The project is divided into 4 work packages (WP) corresponding to:

WP1: Preclinical development of