Mimobody

Since the nineties, monoclonal antibodies (mAb) have emerged as a promising class of pharmaceuticals for the treatment of many human diseases including cancer. MAbs such as IgG (immunoglobulin G) are proteins that comprise two essential domains: an epitope recognition part that is composed of the complementary-determining regions (CDRs), and the Fc region that activates the immune system. These mAbs can block tumor growth, activate tumor lysis by immunoactivation or by coupling to toxins. However, few mAbs are being used in human therapy a quarter century after their discovery. They are widely used as diagnostic and research reagents but their introduction into human therapy has been much slower: today, only 11 mAbs were marketed and used in oncology. Manufacture of mAbs requires a special handling and a costly biotech production procedure. The cost of mAb therapy is a major limiting factor with annual costs of about US$ 100,000 per patient leading to serious concerns about its economical pertinence. Beside this problem however, like most of proteins, many factors, such aggregation, large size, and immunogenicity, limit their use for therapy. Consequently, there is a pressing need for new molecular systems that integrate mAb properties. This challenge can be achieved by designing small antibody mimics by using an entire synthetic approach. Previously, our laboratory has designed and synthesized biomolecular systems based on cyclopeptide scaffolds endowed with tumor-targeting functions that enable the specific delivery of toxic molecules, or imaging probes, or a combination thereof, to malignant tissues. To have access to such sophisticated biomolecular compounds, we have developed new chemical strategies for the synthesis of well-defined biomolecular assemblies using orthogonal chemoselective ligations. In the Mimobody project, we propose to capitalize on these previous studies to prepare small synthetic antibody mimics (named Mimobody), through two IgG examples: Rituximab (Rituxan®) indicated for the treatment of patients with non-Hodgkin's lymphoma, and Cetuximab (Erbitux®) indicated for treatment of carcinoma. It is conceivable to design antibody mimics based on the analysis of the crystal structure of the mAb in complex with its epitope. By transferring the recognition domain (CDR fragments) from the mAb to a synthetic scaffold, it is possible to provide a new class of pharmaceuticals and an alternative to antibodies.