Sarclisa

Isatuximab is an immunoglobulin G1 (IgG1)-derived monoclonal antibody that binds to a specific extracellular epitope of cluster of differentiation 38 (CD38) receptor and triggers several mechanisms leading to the death of CD38 expressing tumuor cells.CD38 is a transmembrane glycoprotein with ectoenzymatic activity, expressed in haematological malignancies, and is highly and uniformly expressed on multiple myeloma cells.Isatuximab acts through immunoglobulin G fragment crystallisable (IgG Fc)-dependent mechanisms including: antibody dependent cell mediated cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP), and complement dependent cytotoxicity (CDC). Isatuximab can also trigger tumuor cell death by induction of apoptosis via an Fc-independent mechanism.In human peripheral blood mononuclear cells (PBMCs), natural killer (NK) cells express the highest CD38 levels. In vitro, isatuximab can activate NK cells in the absence of CD38 positive target tumour cells through a mechanism which is dependent of the Fc portion of isatuximab. Also, isatuximab inhibits regulatory T cells (Tregs) which express higher levels of CD38 in multiple myeloma patients compared to healthy individuals.Isatuximab blocks the enzymatic activity of CD38 which catalyses the synthesis and hydrolysis of cyclic ADP-ribose (cADPR), a calcium mobilising agent, and this may contribute to immunoregulatory functions. Isatuximab inhibits the cADPR production from extracellular nicotinamide adenine dinucleotide (NAD) in multiple myeloma cells.The combination of isatuximab and pomalidomide in vitro enhances cell lysis of CD38 expressing multiple myeloma cells by effector cells (ADCC), and by direct tumour cell killing compared to that of isatuximab alone. In vivo experiments using a human multiple myeloma xenograft model demonstrated that the combination of isatuximab and pomalidomide results in enhanced antitumour activity compared to the activity of isatuximab or pomalidomide alone.