TOL101

TOL101

Monoclonal antibody
Type	Whole antibody
Source	Mouse
Target	αあるふぁβべーた T Cell Receptor
Clinical data
Routes of administration	Intravenous
Legal status
Legal status	US: Investigational New Drug (Renal Transplantation)
Identifiers
CAS Number	0113923AB Y
ChemSpider	none
UNII	28X0AGG6P8
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TOL101, is a murine-monoclonal antibody specific for the human αあるふぁβべーた T cell receptor. In 2010 it was an Investigational New Drug under development by Tolera Therapeutics, Inc.

Clinical progress

TOL101 is a clinical stage investigational drug. The safety and efficacy of TOL101 is currently the focus of a phase 2 clinical trial in renal transplant patients.[1]

Orphan drug status

TOL101 was granted "orphan drug" status [2] 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 αあるふぁβべーた T cells with TOL101 may reduce these issues through two mechanisms. First, infections are expected to be reduced through the preservation of γがんまδでるた 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 when targeting the αあるふぁβべーた TCR because, unlike CD3 proteins, the αあるふぁβべーた TCR contains none of the immunoreceptor tyrosine-based activation motifs (ITAMS) required for T cell activation.

Mechanism of action

TOL101 modulates αあるふぁβべーた T cells

TOL101 has been shown in in vitro models to specifically modulate αあるふぁβべーた T cells. Incubation of peripheral blood monocytes (PBMC) with TOL101 triggers rapid down modulation of the T cell receptor. 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.

αあるふぁβべーた T cells antibodies in experimental disease models

Targeting αあるふぁβべーた T cells with antibodies has been tested in numerous experimental models of disease. The data suggests that in models of multiple sclerosis (Experimental autoimmune encephalomyelitis) and type 1 diabetes (Non-obese diabetic mice,) anti-αあるふぁβべーた TCR antibody therapy can ameliorate disease symptoms and progression. The precise mechanism through which this occurs remains to be defined, however, it is likely to involve the induction of operational tolerance.

Chemistry

TOL101 is a murine IgM antibody.