| March 12, 2001
Penn Receives $1.2 Million Grant
for Further Development of Compstatin, A Drug to Halt
an Overzealous Immune System
(Philadelphia, PA) - In
some ways, the body's first line of defense can also
be its worst enemy. The complement system is a series
of biochemical reactions that activate in response to
foreign molecules and is an important part of the immune
system. Unfortunately, when it is activated at the wrong
time, complement is also responsible for organ transplant
rejection and a long list of diseases.
Researchers at the University of Pennsylvania Medical
Center have found a way to control complement with Compstatin,
a small molecule that blocks the reactions involved
in a complement response. The National Institute for
General Medical Sciences (NIGMS) has awarded John D.
Lambris, PhD, a professor in the Department of Pathology
& Laboratory Medicine, a $1.2 million grant to continue
the development of Compstatin into an effective drug.
"Among the compounds we have studied, I believe Compstatin
holds real promise," said Lambris. "Until Compstatin,
most complement inhibitors were either only marginally
effective or actually toxic to humans."
Part of the reason it has been so difficult to control
complement is because of the complex nature of the human
immune system. Complement proteins serve as a passive
alarm system, watching for pathogens that may enter
the blood system. When a complement protein finds something
it does not recognize, it attaches itself to the invader,
summoning the full wrath of the immune system, which
attempts to destroy the invader. Complement is not a
simple sequence of reactions either, but a series of
interlocking cascades, or chain reactions, of biochemical
events involving at least 30 proteins.
"Fortunately, there is a point where all the protein
cascades intersect," said Lambris. "We figured that
if we can stop the cascade at this point, we can halt
the reaction regardless of what pathway started it."
Lambris and his colleagues focused on one particular
complement protein, an enormous molecule called C3.
They created billions of protein fragments and searched
for ones that might bind to the C3 protein and inactivate
it. Amazingly, they found a ring-shaped protein, made
up of 11 amino acids, which, despite its relatively
small size, inactivated C3 entirely. Lambris named the
"Since C3 was so large, we assumed that we would find
many different fragments that would bind to C3, and
from them we would learn more about the important functional
parts of the molecule," said Lambris. "Instead, out
of all the possibilities we find the one fragment that
attaches directly to C3 and disables it."
Compstatin owes its effectiveness - and potential use
as a therapeutic - to its small size. Compstatin's ring
structure makes it resistant to proteases, enzymes that
destroy proteins, so it is less likely to be broken
down before it meets its target. Smaller molecules like
Compstatin are also more readily adaptable to use as
an oral medication.
Lambris and his colleagues have already demonstrated
Compstatin's abilities in the laboratory, and the NIGMS
grant makes further exploration possible.
"Compstatin has great potential as a complement inhibitor,"
said Mark Tykocinski, MD, Chair of Penn's Department
of Pathology and Laboratory Medicine. "Developing complement
inhibitors with therapeutic potential has been a long-standing
goal of medical science, and such agents could contribute
significantly to the treatment of an array of human
Although the complement proteins are part of the immune
system, they do not always limit themselves to potentially
disease-causing invaders - complement does not discriminate
between bacteria and transplanted organs or even implanted
surgical devices. Complement can also attack healthy
tissue, and a variety of diseases are associated with
complement gone awry, such as multiple sclerosis and
hemolytic anemia. In addition, complement is thought
to play a role in the destruction of cells during strokes,
heart attacks, and burn injuries.
The University of Pennsylvania Health System is distinguished
not only by its historical significance - first hospital
(1751), first medical school (1765), first university
teaching hospital (1874), first fully integrated academic
health system (1993) - but by its position as a major
player on the world stage of medicine in the 21st century.
Penn ranks second among all American medical schools
that receive funds from the National Institutes of Health,
perhaps the single most important barometer of research
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