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|Target||αβ T Cell Receptor|
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Orphan drug status
TOL101 was granted "orphan drug" status  by the U.S. Food and Drug Administration for the treatment of recent onset immune-mediated Type 1 diabetes and for prophylaxis of acute rejection of solid organ transplantation.
Rationale for development
There are numerous agents currently under investigation that are capable of modulating T cells. Currently used agents include anti-thymocyte globulin(ATG) and alemtuzumab, which not only affect T cells, but are also capable of modulating many other aspects of the immune system, often resulting in long-term broad spectrum immune suppression. Antibodies specific for CD3 such as teplizumab and otelixizumab show increased specificity for T cells compared to ATG and alemtuzumab, but are still associated with infection and cytokine release syndrome. Targeting the αβ T cells with TOL101 may reduce these issues through two mechanisms. First, infections are expected[by whom?] to be reduced through the preservation of γδ T cells, which have been shown to play an important role in controlling viruses such as cytomegalovirus (CMV), often observed in antibody treated patients. Second, reductions in cytokine release are expected[by whom?] when targeting the αβ TCR because, unlike CD3 proteins, the αβ TCR contains none of the immunoreceptor tyrosine-based activation motifs (ITAMS) required for T cell activation.
Mechanism of action
TOL101 modulates αβ T cells
TOL101 has been shown in in vitro models to specifically modulate αβ T cells. Incubation of peripheral blood monocytes (PBMC) with TOL101 triggers rapid down modulation of the T cell receptor.[verification needed] Importantly, this occurs without T cell proliferation or cytokine induction. Examination of the ability of TOL101 to modulate T cells in a humanized mouse model not only confirmed these in vitro results but also suggested that the T cell modulating capability of the drug occurred in a non-depletional fashion.
αβ T cells antibodies in experimental disease models
Targeting αβ T cells with antibodies has been tested in numerous experimental models of disease. The data suggest that in models of multiple sclerosis (Experimental autoimmune encephalomyelitis) and type 1 diabetes (Non-obese diabetic mice,) anti-αβ TCR antibody therapy can ameliorate disease symptoms and progression.[verification needed] The precise mechanism through which this occurs remains to be defined, however, it is likely to involve the induction of operational tolerance.
TOL101 is a murine IgM antibody.
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