Abstract EN:

In the era of certain therapeutic antibodies coming of age, there is a medical need to generate new treatment modalities, engineered antibodies or derived fragments that might offer a new option. A classical antibody is a Y-shaped protein composed of two structurally independent parts, the variable region (V-region), and the constant region, (Fc). The V-region is responsible for targeting a specific antibody to an antigen and is different for every type of antibody. The Fc region does not interact with antigens, but rather interacts with components of the immune system through a variety of receptors on immune and other cells. These interactions allow antibodies to regulate the immune response and levels of cell-killing ability, or cytotoxicity, as well as their persistence in circulation and tissues. Fc regions are the same and interchangeable from antibody to antibody. Engineering of the Fc has been demonstrated to improve the serum half-life of antibodies in preclinical and clinical studies and potentially can improve tissue distribution.Camelids, more specifically llamas, produce highly diverse panels of antibodies with a high human homology, or similarity, in their V-regions. The use of their conventional antibodies allows to access and explore a broad selection of targets, including novel and complex targets, while minimizing the time associated with generating and optimizing antibody candidates using more traditional methods. We have applied several technologies to create antibodies with optimized V-regions and an enhanced Fc region for the chosen target.The aim of this thesis is to confirm the hypothesis that therapeutic antibodies issued from research on camelids, equipped with various Fc engineering technologies may offer a new potential option for clinical setting. Two examples will be analysed to confirm the hypothesis.The first example is Efgartigimod, the engineered human Fc fragment that functions as an antagonist of FcRn that was developed for the treatment of patients with myasthenia gravis, immune thrombocytopenia and pemphigus vulgaris, all of which are rare and severe autoimmune diseases associated with high levels of circulating pathogenic IgG antibodies for which a severe, yet unmet medical need exists. By introducing a series of mutations in the CH2 and CH3 regions that increase the affinity for FcRn at the low pH of the endosome and the neutral pH of the circulation Efgartigimod is designed to block the recycling of IgG antibodies, which results in their rapid clearance.The second example is cusatuzumab, the SIMPLE antibody against CD70, which is Fc engineered (afucosylated) resulting in increased antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Cusatuzumab was developed for cancer indications, initially for cutaneous T-cell lymphoma (TCL) and acute myeloid leukaemia (AML) as well as high-risk myeloid dysplastic syndrome (MDS). TCL and AML are rare and aggressive haematological cancers for which significant also unmet medical need exists. MDS, a rare bone marrow disorder, is often a precursor to AML. Cusatuzumab is an antibody designed to potently block the CD70/CD27 interaction and kill CD70-positive cells via its potent antibody effector functions.Several clinical trials were performed and analysed to confirm the hypothesis. Results will be discussed and compared with the available literature.