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{{Short description|Monoclonal antibody}} |
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{{Orphan|date=September 2010}} |
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{{Update|date=October 2021}} |
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{{Drugbox |
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{{Drugbox |
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| CAS_number_Ref = {{cascite|correct|CAS}} |
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| verifiedrevid = 424804111 |
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| CAS_number = 0113923AB |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = 28X0AGG6P8 |
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| verifiedrevid = 451563029 |
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<!--Monoclonal antibody data--> |
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<!--Clinical data--> |
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| tradename = |
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| legal_status = Investigational New Drug (Renal Transplantation) |
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| legal_US = Investigational New Drug |
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| legal_US_comment = (Renal Transplantation) |
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| routes_of_administration = Intravenous |
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| routes_of_administration = Intravenous |
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<!--Chemical data--> |
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| ChemSpiderID = none}} |
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'''TOL101''', is a ]-] ] specific for the human ]. In 2010 it was an ] under development by ], Inc. |
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'''TOL101''', is a ]-] ] specific for the human ]. In 2010 it was an ] under development by ], Inc. |
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==Clinical progress== |
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==Clinical progress== |
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TOL101 is a clinical stage investigational drug. The safety and efficacy of TOL101 is currently the focus of a ] in ] patients. |
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TOL101 is a clinical stage investigational drug. The safety and efficacy of TOL101 is currently the focus of a ] in ] patients.{{When|date=October 2021}} |
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==Orphan drug status== |
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==Orphan drug status== |
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TOL101 was granted "orphan drug" status by the ] for the treatment of recent onset immune-mediated ] and for ] of ] of ] ]ation. |
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TOL101 was granted "orphan drug" status by the ] for the treatment of recent onset immune-mediated ] and for ] of ] of ] ]ation.{{When|date=October 2021}} |
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==Rationale for development== |
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==Rationale for development== |
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There are numerous agents currently under investigation that are capable of modulating T cells. Currently used agents include ](ATG) and ], 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=] |volume=355|issue=19 |pages=1967–77 |pmid=17093248 }}</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=] |volume=21|issue=7 |pages=1387–94}}</ref> Antibodies specific for ] such as ] and ]<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=] |volume=6 |issue=3 |pages=149–157}}</ref> show increased specificity for T cells compared to ATG and ], but are still associated with infection and ]. Targeting the ]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 ]s<ref>{{Cite journal|pmid=18406365 |doi=10.1016/j.imbio.2007.10.006 |author=Beetz S, Wesch D, Marischen L, Welte S, Oberg HH, Kabelitz D |year=2008 |title=Innate immune functions of human gammadelta T cells |journal=] |volume=213|issue=3-4 |pages=173–82}}</ref>, which have been shown to play an important role in controlling viruses such as ] (CMV),<ref>{{Cite journal|doi=10.1086/322843|pmid=11494158 |author=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=] |volume=184|issue=5 |pages=533–41}}</ref>, often observed in antibody treated patients. Second, reductions in ] release are expected{{By whom|date=September 2010}} when targeting the αβ TCR because, unlike ], the αβ TCR contains none of the ]s (ITAMS) required for T cell activation.{{Citation needed|date=September 2010}} |
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There are numerous agents currently under investigation that are capable of modulating T cells. Currently used agents include ](ATG) and ], 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=] |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=] |volume=21|issue=7 |pages=1387–94|doi-access=free }}</ref> Antibodies specific for ] such as ] and ]<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=] |volume=6 |issue=3 |pages=149–157|s2cid=30916593 }}</ref> show increased specificity for T cells compared to ATG and ], but are still associated with infection and ]. Targeting the ]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 ]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=] |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 ] (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=] |volume=184|issue=5 |pages=533–41|doi-access=free }}</ref> often observed in antibody treated patients. Second, reductions in ] release are expected{{By whom|date=September 2010}} when targeting the αβ TCR because, unlike ], the αβ TCR contains none of the ]s (ITAMS) required for T cell activation.{{Citation needed|date=September 2010}} |
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==Mechanism of action== |
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==Mechanism of action== |
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=== TOL101 modulates αβ T cells === |
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=== TOL101 modulates αβ T cells === |
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TOL101 has been shown in ''in vitro'' models to specifically modulate αβ T cells. Incubation of ]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=] |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|author=Getts DR, Martin A, Siemionow M, Miller SD |title=Operational tolerance vs immune suppression, targeting the αβ TCR with TOL101 |journal=] |volume=10 |issue=Suppl 4 1-608, LB07 }}</ref> |
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TOL101 has been shown in ''in vitro'' models to specifically modulate αβ T cells. Incubation of ]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=] |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=] |volume=10 |issue=Suppl 4 1–608, LB07 }}</ref> |
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===αβ T cells antibodies in experimental disease models=== |
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===αβ T cells antibodies in experimental disease models=== |
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Targeting αβ T cells with antibodies has been tested in numerous experimental models of disease. The data suggest that in models of ] (]<ref>{{Cite journal|doi=10.1111/j.1365-3083.2006.01866.x|pmid=17212765 |author=Lavasani S, Dzhambazov B, ''et al.'' |year=2007 |title=Monoclonal antibody against T-cell receptor alphabeta induces self-tolerance in chronic experimental autoimmune encephalomyelitis |journal=] |volume=65 |issue=1 |pages=39–47}}</ref>) and ] (Non-obese diabetic mice,<ref>{{Cite journal|doi=10.1002/eji.1830210511 |author=Sempe P, ''et al.'' |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=] |volume=21|issue=5 |pages=1163–9 |year=1991 }}</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}} |
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Targeting αβ T cells with antibodies has been tested in numerous experimental models of disease. The data suggests that in models of ] (]<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=] |volume=65 |issue=1 |pages=39–47|doi-access=free }}</ref>) and ] (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=] |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}} |
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==Chemistry== |
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==Chemistry== |
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==References== |
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==References== |
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{{Reflist}} |
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{{Reflist}} |
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{{Use dmy dates|date=September 2010}} |
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{{Use dmy dates|date=April 2020}} |
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{{Portal bar|Medicine|Chemistry|Government|Society}} |
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{{Authority control}} |
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{{DEFAULTSORT:Tol101}} |
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