More recently, the finding of CD6 as a susceptibility gene in multiple sclerosis, a prototypic autoimmune disease [[28], [29] and [30]], supports the role of CD6 in pathological autoimmunity leading to tissue inflammation and reinforces its relevance for targeted therapy. It is worth noting that the therapeutic effectiveness of anti-human CD6 mAbs has been primarily

associated with their ability to deplete CD6 cells by a complement-mediated mechanism [27] or the capacity of blocking the interaction between CD6 and its ligand ALCAM [31,32]. However, several evidences suggest that signals delivered upon stimulation of different epitopes of the CD6 molecule may produce different effects on T cells [21,33]. Itolizumab Vemurafenib chemical structure (T1h) is a humanized monoclonal antibody [34] that recognizes the membrane-distal domain (SRCR1) of CD6 [35]. In in vitro experiments using a soluble construction of the ALCAM molecule, it was shown that T1h does not inhibit ALCAM binding to T-cells. Furthermore, it was shown that T1h does not produce T-cell depletion [ 35]. In spite of these properties, in vitro characterization showed that itolizumab inhibits the T-cell proliferation induced in the presence

of ALCAM and excess IL-2, downregulates the phosphorylation of intracellular proteins implicated in the CD6-mediated activation pathways and reduces interferon-γ, IL-6 and TNF-α production [ 20]. Hence, targeting CD6 in vivo with itolizumab would modulate the immune response by reducing T-cell activation, proliferation and pro-inflammatory responses. It is remarkable that these inmunomodulatory buy Target Selective Inhibitor Library effects are produced without inhibiting ligand binding and inducing T cell depletion. In this regards, it has been reported that there are antibodies which instead

of preventing ligand binding may cause receptor binding to be non-productive. These Methisazone interactions can result in either an inhibition of new receptor formation, stimulation of the loss of existing receptors, or a blockage followed by internalization or downregulation of the receptors [36]. On the other hand, nondepleting mAbs have been used to establish persistent T-cell tolerance [37]. All together, these findings point to a potential new mechanism of action for itolizumab, as compared with other anti-human CD6 mAb previously used in clinical studies and other anti-CD6 antibodies assayed in preclinical studies [21,22,38]. The parent antibody of itolizumab, the murine mAb ior T1, was raised in BALB/c mice immunized with PBMCs from a patient with Sezary’s syndrome [39,40]. Ior T1 mAb showed therapeutic effects in autoimmune diseases, such as psoriasis and RA [23,24,[41], [42] and [43]]. However, due to its murine origin this antibody needed to be humanized aiming to eliminate most of the undesired properties of murine mAbs [34].