TOL101

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TOL101 ?
Monoclonal antibody
Type Whole antibody
Source Mouse
Target αβ T Cell Receptor
Clinical data
Legal status Investigational New Drug (Renal Transplantation)
Routes Intravenous
Identifiers
ATC code ?
Chemical data
Formula ?
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TOL101, is a murine-monoclonal antibody specific for the human αβ T cell receptor. In 2010 it was an Investigational New Drug under development by Tolera Therapeutics, Inc.

Clinical progress[edit]

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[edit]

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[edit]

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.[1][2] Antibodies specific for CD3 such as teplizumab and otelixizumab[3] 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,[4] which have been shown to play an important role in controlling viruses such as cytomegalovirus (CMV),[5] 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.[citation needed]

Mechanism of action[edit]

TOL101 modulates αβ T cells[edit]

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.[6][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.[7]

αβ T cells antibodies in experimental disease models[edit]

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[8]) and type 1 diabetes (Non-obese diabetic mice,[9]) 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.[citation needed]

Chemistry[edit]

TOL101 is a murine IgM antibody.

References[edit]

  1. ^ Brennan, DC, Daller JA, Lake KD, Cibrik D, Del Castillo D (2006). "Rabbit antithymocyte globulin versus basiliximab in renal transplantation". N Engl J Med 355 (19): 1967–77. doi:10.1056/NEJMoa060068. PMID 17093248. 
  2. ^ Mohty M (2007). "Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond". Leukemia 21 (7): 1387–94. doi:10.1038/sj.leu.2404683. PMID 17410187. 
  3. ^ Chatenoud L (2010). "Immune therapy for type 1 diabetes mellitus-what is unique about anti-CD3 antibodies?". Nature Reviews Endocrinology 6 (3): 149–157. doi:10.1038/nrendo.2009.275. PMID 20173776. 
  4. ^ Beetz S, Wesch D, Marischen L, Welte S, Oberg HH, Kabelitz D (2008). "Innate immune functions of human gammadelta T cells". Immunobiology 213 (3–4): 173–82. doi:10.1016/j.imbio.2007.10.006. PMID 18406365. 
  5. ^ Lafarge X, Merville P, Cazin MC, Berge F, Potaux L, Moreau JF, Dechanet-Merville J (2001). "Cytomegalovirus infection in transplant recipients resolves when circulating gammadelta T lymphocytes expand, suggesting a protective antiviral role". J Infect Dis 184 (5): 533–41. doi:10.1086/322843. PMID 11494158. 
  6. ^ Getts DR, Brown S, Siemionow M, Miller, SD. "TOL101; a new aid to prevent allograft rejection". American Journal of Transplantation 9 (Suppl 2): 991–766, LB26. 
  7. ^ Getts DR, Martin A, Siemionow M, Miller SD. "Operational tolerance vs immune suppression, targeting the αβ TCR with TOL101". American Journal of Transplantation 10 (Suppl 4 1–608, LB07). 
  8. ^ Lavasani S, Dzhambazov B, et al. (2007). "Monoclonal antibody against T-cell receptor alphabeta induces self-tolerance in chronic experimental autoimmune encephalomyelitis". Scandinavian Journal of Immunology 65 (1): 39–47. doi:10.1111/j.1365-3083.2006.01866.x. PMID 17212765. 
  9. ^ Sempe P, et al. (1991). "Anti-alpha/beta T cell receptor monoclonal antibody provides an efficient therapy for autoimmune diabetes in non-obese diabetic (NOD) mice". Eur J Immunol 21 (5): 1163–9. doi:10.1002/eji.1830210511. PMID 1828030.