Unique Properties of T-Guard™
Although the principle of immunotoxins as such is not new, the particular combination of the two immunotoxins selected for the construction of T-Guard offer some unique benefits that are found in no other product on the market today:
The combination of half a dose of the anti-CD3 and anti-CD7 immunotoxin turns out to be more efficient in eliminating T cells than either immunotoxin alone. Apparently, the simultaneous targeting via two distinct antigens reduces the chance of T cells escaping treatment. Equally important, dividing the clinical dose over two different immuntoxins appears to dilute unwanted side effects. Both these features increase the therapeutic window as compared to the single immunotoxin products clinically tested so far.
Multiple (Gentle) Mechanisms of T Cell Elimination
Both the anti-CD3 and anti-CD7 mAb deliver the RTA toxin to the inside of T cells, resulting in the elimination of these cells by protein synthesis inhibition (Figure 1). On top of that, the mere binding of the anti-CD3 mAb to the T cell receptor/CD3 complex (TCR/CD3) results in an immunosuppressive effect through modulation/blocking of the TRC/CD3 and by ‘Activation Induced Cell death (AICD)’. Both these mechanisms result in a ‘gentle’ (non-inflammatory) elimination of T cells through apoptosis (controlled cell death). Also important in this respect is that the anti-CD3 mAb selected for T-Guard does not stimulate T cells. These characteristics strongly reduce the occurrence of cytokine release syndrome (CRS), a potentially life-threatening complication frequently associated with alternative antibody immunosuppressants.
Narrow Specificity and Short Half-Life
T-Guard has a narrow specificity, directed only against mature T cells and NK cells. Importantly, activated T cells (the ‘trouble makers’) turn out to be about 35-times more vulnerable than non-activated T cells. Although not a black and white phenomenon, this might prove advantageous when treating critically ill patients. Ideally, T-Guard stops the pathologic immune response, but will (relatively) spare the resting T-cell pool with its ability for countering future hazardous infections. The elimination of NK cells is thought to be beneficial as these lymphocytes might aggravate the severity of acute GVHD through cytokine production. Competitive products like Anti -Thymocyte Globulin (ATG) and Campath® (Alemtuzumab) have a far broader specificity, as they do not only target T- and NK cells, but also B cells, macrophages and dendritic cells.
T-Guard is administered as four infusions in a one-week treatment course. Due to its short half-life, about seven hours, T-Guard will be rapidly washed out after the last infusion, allowing the swift restoration of the T-cell compartment with newly formed (non-disease causing) cells. As a consequence, the immunosuppression induced by T-Guard will not only be less broad, but also of shorter duration than as compared to competitive antibody immunosuppressants, which typically have a serum half-life of weeks rather than hours. This is considered of vital importance, as the use of current antibody immunosuppressents is often associated with an increased overall incidence of opportunistic infections and a significantly delayed T cell recovery.
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