TOL101, is a
murine
The Old World rats and mice, part of the subfamily Murinae in the family Muridae, comprise at least 519 species. Members of this subfamily are called murines. In terms of species richness, this subfamily is larger than all mammal families excep ...
-
monoclonal
Monoclonality refers to the state of a line of cells that have been derived from a single clonal origin. Thus "monoclonal cells" can be said to form a single clone. The term ''monoclonal'' comes from the Ancient Greek ''monos'', meaning "alone" o ...
antibody
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
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
The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...
in
renal transplant
Kidney transplant or renal transplant is the organ transplant of a kidney into a patient with end-stage kidney disease (ESRD). Kidney transplant is typically classified as deceased-donor (formerly known as cadaveric) or living-donor transplantati ...
patient
Orphan drug status
TOL101 was granted "orphan drug" statu
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
Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for ...
and for
prophylaxis
Preventive healthcare, or prophylaxis, consists of measures taken for the purposes of disease prevention.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental hea ...
of
acute rejection
Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient a ...
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
Anti-thymocyte globulin (ATG) is an infusion of horse or rabbit-derived antibodies against human T cells and their precursors (thymocytes), which is used in the prevention and treatment of Transplant rejection, acute rejection in organ transplant ...
(ATG) and
alemtuzumab
Alemtuzumab, sold under the brand names Campath and Lemtrada among others, is a medication used to treat chronic lymphocytic leukemia (CLL) and multiple sclerosis. In CLL, it has been used as both a first line and second line treatment. In MS it ...
, 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
Teplizumab, sold under the brand name Tzield, is a humanized anti-CD3 monoclonal antibody that is the first approved treatment indicated to delay the onset of stage 3 type 1 diabetes (T1D) in people with stage 2 T1D.
The Fc region of this antibod ...
and
otelixizumab
Otelixizumab, also known as TRX4, is a monoclonal antibody, which is being developed for the treatment of type 1 diabetes and other autoimmune diseases. The antibody is being developed by Tolerx, Inc. in collaboration with GlaxoSmithKline and ...
show increased specificity for T cells compared to ATG and
alemtuzumab
Alemtuzumab, sold under the brand names Campath and Lemtrada among others, is a medication used to treat chronic lymphocytic leukemia (CLL) and multiple sclerosis. In CLL, it has been used as both a first line and second line treatment. In MS it ...
, but are still associated with infection and
cytokine release syndrome
Cytokine release syndrome (CRS) is a form of systemic inflammatory response syndrome (SIRS) that can be triggered by a variety of factors such as infections and certain drugs. It refers to cytokine storm syndromes (CSS) and occurs when large numb ...
. 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
''Cytomegalovirus'' (''CMV'') (from ''cyto-'' 'cell' via Greek - 'container' + 'big, megalo-' + -''virus'' via Latin 'poison') is a genus of viruses in the order ''Herpesvirales'', in the family ''Herpesviridae'', in the subfamily ''Betaherpe ...
(CMV), often observed in antibody treated patients. Second, reductions in
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
release are expected when targeting the αβ TCR because, unlike
CD3 proteins, the αβ TCR contains none of the
immunoreceptor tyrosine-based activation motif An immunoreceptor tyrosine-based activation motif (ITAM) is a conserved sequence of four amino acids that is repeated twice in the cytoplasmic tails of non-catalytic tyrosine-phosphorylated receptors, cell-surface proteins found mainly on immune cel ...
s (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
Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
(
Experimental autoimmune encephalomyelitis
Experimental autoimmune encephalomyelitis, sometimes experimental allergic encephalomyelitis (EAE), is an animal model of brain inflammation. It is an inflammatory demyelinating disease of the central nervous system (CNS). It is mostly used with ro ...
) and
type 1 diabetes
Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for ...
(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
{{DEFAULTSORT:Tol101
Antibodies
Immunomodulating drugs
Receptor modulators
Experimental drugs