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| {{Short description|Monoclonal antibody}} | |||
| {{Orphan|date=September 2010}} | |||
| {{Update|date=October 2021}} | |||
| {{Drugbox | {{Drugbox | ||
| | CAS_number_Ref = {{cascite|correct|CAS}} | |||
| ⚫ | | verifiedrevid = |
||
| | CAS_number = 0113923AB | |||
| | UNII_Ref = {{fdacite|correct|FDA}} | |||
| | UNII = 28X0AGG6P8 | |||
| ⚫ | | verifiedrevid = 451563029 | ||
| <!--Monoclonal antibody data--> | <!--Monoclonal antibody data--> | ||
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| <!--Clinical data--> | <!--Clinical data--> | ||
| | tradename = | | tradename = | ||
| | |
| legal_US = Investigational New Drug | ||
| | legal_US_comment = (Renal Transplantation) | |||
| | routes_of_administration = Intravenous | | routes_of_administration = Intravenous | ||
| <!--Chemical data--> | <!--Chemical data--> | ||
| | ChemSpiderID = none}} | |||
| }} | |||
| '''TOL101''', is a ]-] ] specific for the human ]. In 2010 it was an ] under development by ], Inc. | '''TOL101''', is a ]-] ] specific for the human ]. In 2010 it was an ] under development by ], Inc. | ||
| ==Clinical progress== | ==Clinical progress== | ||
| TOL101 is a clinical stage investigational drug. The safety and efficacy of TOL101 is currently the focus of a ] in ] patients. | 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}} | ||
| ==Orphan drug status== | ==Orphan drug status== | ||
| TOL101 was granted "orphan drug" status by the ] for the treatment of recent onset immune-mediated ] and for ] of ] of ] ]ation. | 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}} | ||
| ==Rationale for development== | ==Rationale for development== | ||
| 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 | |
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}} | ||
| ==Mechanism of action== | ==Mechanism of action== | ||
| === TOL101 modulates αβ T cells === | === TOL101 modulates αβ T cells === | ||
| 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| |
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> | ||
| ===αβ T cells antibodies in experimental disease models=== | ===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 |
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}} | ||
| ==Chemistry== | ==Chemistry== | ||
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| ==References== | ==References== | ||
| {{Reflist}} | {{Reflist}} | ||
| {{Use dmy dates|date= |
{{Use dmy dates|date=April 2020}} | ||
| {{Portal bar|Medicine|Chemistry|Government|Society}} | |||
| {{Authority control}} | |||
| {{DEFAULTSORT:Tol101}} | {{DEFAULTSORT:Tol101}} | ||
| ] | ] | ||
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| ] | ] | ||
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Latest revision as of 05:29, 22 January 2024
Monoclonal antibody | This article needs to be updated. Please help update this article to reflect recent events or newly available information. (October 2021) |
| Monoclonal antibody | |
|---|---|
| Type | Whole antibody |
| Source | Mouse |
| Target | αβ T Cell Receptor |
| Clinical data | |
| Routes of administration | Intravenous |
| Legal status | |
| Legal status |
|
| Identifiers | |
| CAS Number | |
| ChemSpider |
|
| UNII | |
| (verify) | |
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.
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 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 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. 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 suggests 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. 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.
References
- 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.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - 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.
- 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. S2CID 30916593.
- 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.
- 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.
- 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.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - 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).
- 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.
- 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. S2CID 72955769.
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