TOL101

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.

TOL101
Monoclonal antibody
TypeWhole antibody
SourceMouse
Targetαβ T Cell Receptor
Clinical data
Routes of
administration		Intravenous
Legal status
Legal status
Identifiers
CAS Number
ChemSpider
  • none
UNII
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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.[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 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 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.[6] 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

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[8]) and type 1 diabetes (Non-obese diabetic mice,[9]) 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
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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. S2CID 30916593.
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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. S2CID 72955769.

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