YSM Issue 94.2

FOCUS
Medicine
A BREAKTHROUGH TH
Could teplizumab lead us to a cure for typ
Before insulin was discovered in 1922
by Sir Frederick Banting and Charles
Best, type 1 diabetes—an autoimmune
disease that renders the body unable to
convert blood sugars to energy—was often a
death sentence. Patients with diabetes rarely
lived for more than two years after disease
onset. This discovery of the insulin treatment
was revolutionary: for the first time, patients
could survive and manage their illness.
Nearly a century later, a new
breakthrough in the field of type 1
diabetes has been achieved. A clinical
trial analysis published in Science
Translational Medicine, co-authored by
Kevan Herold, C.N.H. Long Professor of
Immunology and of Internal Medicine
at Yale University, and Emily Sims,
Assistant Professor of Pediatrics at
Indiana University, reported compelling
evidence for teplizumab—a drug granted
FDA ‘Breakthrough’ status in January
2021. The breakthrough aspect comes
from the fact that this drug doesn’t
simply address symptoms; it could be
able to preemptively delay, or even
prevent, type 1 diabetes altogether.
The journey towards teplizumab has
been a long and arduous one. “Literally
for the past thirty years I’ve been working
on this, from doing the pre-clinical mouse
work, to doing the early investigatorinitiated
clinical trials, to eventually
leading clinical trials that were done by
NIH consortia like the Immune Tolerance
Network or TrialNet,” Herold said.
A Long and Winding Road
Even after insulin started to be used as
treatment, Herold witnessed the drastic
effects that the disease had on the quality
of life of patients. “Diabetes is with you
twenty-four-seven,” he said. “There’s literally
nothing that you do that is not impacted by
having the disease, whether it’s deciding to
eat or not, whether it’s exercise, whether it’s
sleep, whether it’s going to class.”
For Herold, the prospect of conducting
research had been appealing since his
undergraduate years. Throughout his
research trajectory, he has always strived to
understand the basic mechanisms, causes,
and treatments of type 1 diabetes. Herold’s
decades-long commitment to the pursuit
of scientific advancement in this area began
even before the invention of many essential
research techniques scientists often rely on
today, such as polymerase chain reaction. “At
that time, a lot of what we take for granted now
hadn’t even been discovered,” he explained.
“Immunology was still in its infancy.”
The research leading up to this
breakthrough drug began in 1990
for Herold and his colleague, Jeffrey
Bluestone, Professor of Metabolism and
Endocrinology at UCSF. In his earlier
research, Herold had studied autoreactive
T cells—a group of immune white blood
cells that turn against our own cells and
tissues. By looking at them in mouse
models with diabetes, he was led to believe
that they could cause type 1 diabetes in
humans. With researchers at Johnson
& Johnson, Bluestone then developed a
human drug, teplizumab, that modifies
a certain population of autoreactive T
cells that play an important role in killing
beta cells—the cells that produce insulin
in the pancreas. CD3, a T cell receptor, is
involved in activating this population of
autoreactive T cells. Teplizumab is an anti-
CD3 antibody that binds competitively to
CD3—an action thought to prevent the
receptor from binding to and activating the
autoreactive T cells. Teplizumab thus serves
as a regulatory immunosuppressant for an
overactive immune system, protecting
against the depletion of beta-cells that is
characteristically seen in type 1 diabetes.
From Gold, to Dirt, and Back
Teplizumab showed early success in
Herold’s first clinical trial in 2002 and was
later acquired by biotechnology company
MacroGenics. It was also supported by
the pharmaceutical company Eli Lilly
in phase III clinical trials to evaluate its
safety and efficacy. However, this large-
PHOTOS COURTESY OF ALEX DONG
16 Yale Scientific Magazine May 2021 www.yalescientific.org