JDRF-funded scientists at Yale
University recently found a mechanism of action by which teplizumab, an
anti-CD3 antibody may be working as an immune therapy for T1D.   

Currently, once T1D starts to develop,
there’s no intervention developed to stop it. The immune system slowly and
inevitably kills the pancreatic beta cells that produce insulin, a hormone that
enables people to get energy from food. As a result, people with T1D have to
test their blood sugar and give themselves insulin (with injections or an
insulin pump) multiple times every day in order to stay alive. What’s more, reversing
T1D remains an elusive and complicated challenge, requiring restoration of the
insulin-producing cells that were destroyed, as well as solutions to turn off
the misguided immune system attack on insulin-producing cells.

Teplizumab, the drug used in the study, is thought to work by
shutting off a part of the immune system most responsible for attacking these
insulin-producing cells and generating long-term immunoregulation to control
this misguided autoimmune response. While previous trials tested whether
teplizumab might preserve insulin production in people recently diagnosed with
T1D, researchers are now also studying whether the drug might preemptively prevent
or delay the development of T1D in at-risk individuals.  One such study is being
conducted by the National Institutes of Health’s Type 1 Diabetes TrialNet.  

The latest findings about teplizumab are reported in the current
issue of the journal Science Translational Medicine.  In
the study, which was funded by JDRF, NIH, Yale University, and the Health
Service Executive of Ireland, researchers led by Dr. Kevan Herold, M.D.,
professor of immunobiology at Yale School of Medicine used a mouse model with a
functional human immune system, and focused on the effect of the drug on T
cells, a critical immune system component involved in the development of
T1D.  The team found that the drug
induced certain T cells to migrate from the circulatory and lymph systems to
the small intestine, where they produced the immunoregulatory protein
interleukin-10 (IL-10).  IL-10 is an important
regulator of the immune
system that has a role in preventing or controlling autoimmune diseases.  These T cells were also converted into
regulatory T-cells, known to be helpful in restoring and maintaining normal
immune system balance.

While researchers have yet to fully understand teplizumab’s potential
role in treatment or prevention of T1D, this study underscores the importance
of understanding the mechanism of action of therapies in translational research
– the ability to effectively convert lab findings into useful therapies in
clinical studies. The work provided important clues about how the
investigational drug works in human cells and demonstrated that humanized mice
can be successfully used to identify how drugs such as this one work in people.
 

By better understanding a therapy’s exact mechanism of
action, it allows researchers to improve the design of future trials, including
developing biomarkers to determine dosing and assess efficacy. In this case,
the Yale study unlocks doors for more studies to explore the extent to which therapies
that target the immune system may prevent the onset of T1D.