View source for TOL101

{{Short description|Monoclonal antibody}}
{{Update|date=October 2021}}
{{Drugbox
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 0113923AB
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 28X0AGG6P8
| verifiedrevid = 451563029
<!--Monoclonal antibody data-->
| type = mab
| mab_type = mab
| source = o
| target = [[T cell receptor|αβ T Cell Receptor]]
<!--Clinical data-->
| tradename =
| legal_US = Investigational New Drug
| legal_US_comment = (Renal Transplantation)
| routes_of_administration = Intravenous
<!--Chemical data-->
| ChemSpiderID = none}}
'''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==
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.{{When|date=October 2021}}[http://www.clinicaltrials.gov/ct2/results?term=tol101]
==Orphan drug status==
TOL101 was granted "orphan drug" status [https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesignation/default.htm] by the [[Food and Drug Administration (United States)|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]] [[Organ transplantation|transplant]]ation.{{When|date=October 2021}}
==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.<ref>{{Cite journal|doi=10.1056/NEJMoa060068 |author=Brennan, DC, Daller JA, Lake KD, Cibrik D, Del Castillo D |year=2006 |title=Rabbit antithymocyte globulin versus basiliximab in renal transplantation |journal=[[N Engl J Med]] |volume=355|issue=19 |pages=1967–77 |pmid=17093248 |doi-access=free }}</ref><ref>{{Cite journal|pmid=17410187 |doi=10.1038/sj.leu.2404683|author=Mohty M |year=2007 |title=Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond |journal=[[Leukemia (journal)|Leukemia]] |volume=21|issue=7 |pages=1387–94|doi-access=free }}</ref> Antibodies specific for [[CD3 (immunology)|CD3]] such as [[teplizumab]] and [[otelixizumab]]<ref>{{Cite journal|pmid=20173776 |doi=10.1038/nrendo.2009.275 |author=Chatenoud L |year=2010 |title=Immune therapy for type 1 diabetes mellitus-what is unique about anti-CD3 antibodies? |journal=[[Nature (journal)|Nature Reviews Endocrinology]] |volume=6 |issue=3 |pages=149–157|s2cid=30916593 }}</ref> 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 cell]]s with TOL101 may reduce these issues through two mechanisms. First, infections are expected{{By whom|date=September 2010}} to be reduced through the preservation of [[γδ T cell]]s,<ref>{{Cite journal|pmid=18406365 |doi=10.1016/j.imbio.2007.10.006 |vauthors=Beetz S, Wesch D, Marischen L, Welte S, Oberg HH, Kabelitz D |year=2008 |title=Innate immune functions of human gammadelta T cells |journal=[[Immunobiology (journal)|Immunobiology]] |volume=213|issue=3–4 |pages=173–82|doi-access=free }}</ref> which have been shown to play an important role in controlling viruses such as [[cytomegalovirus]] (CMV),<ref>{{Cite journal|doi=10.1086/322843|pmid=11494158 |vauthors=Lafarge X, Merville P, Cazin MC, Berge F, Potaux L, Moreau JF, Dechanet-Merville J |year=2001 |title=Cytomegalovirus infection in transplant recipients resolves when circulating gammadelta T lymphocytes expand, suggesting a protective antiviral role |journal=[[J Infect Dis]] |volume=184|issue=5 |pages=533–41|doi-access=free }}</ref> often observed in antibody treated patients. Second, reductions in [[cytokine]] release are expected{{By whom|date=September 2010}} when targeting the αβ TCR because, unlike [[CD3 (immunology)|CD3 proteins]], the αβ TCR contains none of the [[immunoreceptor tyrosine-based activation motif]]s (ITAMS) required for T cell activation.{{Citation needed|date=September 2010}}
==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 monocyte]]s (PBMC) with TOL101 triggers rapid down modulation of the T cell receptor.<ref>{{Cite journal|author=Getts DR, Brown S, Siemionow M, Miller, SD |title=TOL101; a new aid to prevent allograft rejection |journal=[[American Journal of Transplantation]] |volume=9 |issue=Suppl 2 |pages=991–766, LB26}}</ref>{{Verify source|date=September 2010}} 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.<ref>{{Cite journal|vauthors=Getts DR, Martin A, Siemionow M, Miller SD |title=Operational tolerance vs immune suppression, targeting the αβ TCR with TOL101 |journal=[[American Journal of Transplantation]] |volume=10 |issue=Suppl 4 1–608, LB07 }}</ref>
===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 suggests that in models of [[multiple sclerosis]] ([[Experimental autoimmune encephalomyelitis]]<ref>{{Cite journal|doi=10.1111/j.1365-3083.2006.01866.x|pmid=17212765  |vauthors=Lavasani S, Dzhambazov B, etal |year=2007 |title=Monoclonal antibody against T-cell receptor alphabeta induces self-tolerance in chronic experimental autoimmune encephalomyelitis |journal=[[Scandinavian Journal of Immunology]] |volume=65 |issue=1 |pages=39–47|doi-access=free }}</ref>) and [[type 1 diabetes]] (Non-obese diabetic mice,<ref>{{Cite journal|doi=10.1002/eji.1830210511  |vauthors=Sempe P, etal |title=Anti-alpha/beta T cell receptor monoclonal antibody provides an efficient therapy for autoimmune diabetes in non-obese diabetic (NOD) mice|pmid=1828030 |journal=[[Eur J Immunol]] |volume=21|issue=5 |pages=1163–9 |year=1991 |s2cid=72955769 }}</ref>) anti-αβ TCR antibody therapy can ameliorate disease symptoms and progression.{{Verify source|date=September 2010}} The precise mechanism through which this occurs remains to be defined, however, it is likely to involve the induction of operational tolerance.{{Citation needed|date=September 2010}}
==Chemistry==
TOL101 is a murine IgM antibody.
==References==
{{Reflist}}
{{Use dmy dates|date=April 2020}}
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[[Category:Antibodies]]
[[Category:Immunomodulating drugs]]
[[Category:Receptor modulators]]
[[Category:Experimental drugs]]