| March 24, 2003
Teaming Up To Attack Free Radicals
Antibody/Enzyme Combo Protects Transplanted Lungs from
Oxidative Stress Damage
PA) Researchers based at the University of Pennsylvania
School of Medicine have combined the precision of
antibodies with the power of an antioxidant enzyme to
create a new way to protect transplanted lungs from
oxidative stress - also known as free radical damage
- before and during transplantation.
Their findings, presented in the April edition of Nature
Biotechnology and available online now, demonstrate
the therapeutic potential of immunotargeting as a drug
delivery system. Oxidative stress causes some degree
of damage in 15-20% of all transplants and is the leading
cause of acute lung graft failure. By protecting the
lungs from damage, the researchers have determined that
they can increase lung-graft survivability and the length
of time a donated lung can be kept in cold storage.
"It is a simple theory that has been difficult
to put into practice: get an antibody that will go to
a specific target and attach a therapeutic to go along
for the ride," said Vladimir R. Muzykantov,
MD, PhD, assistant professor in Penn's Department
of Pharmacology. "Endothelial cells - the cells
that line the interior of blood vessels - bristle with
possible targets for antibodies to cling to as they
rush through the bloodstream. This targeted delivery
of drugs has enormous potential for treating a variety
of endothelial cell disorders, including cancer and
cardiovascular and pulmonary disease."
To protect transplanted lungs against oxidative stress,
Muzykantov and his colleagues chemically coupled catalase,
an enzyme that detoxifies oxidants, with an antibody
for the platelet-endothelial cell adhesion molecule-1
(PECAM). Their findings in animal models show that anti-PECAM/catalase
hybrid construct strengthened antioxidant defenses,
lessened free-radical damage, reduced transplantation-associated
acute lung injury, and improved the overall survivability
of the lung graft.
"All organs, and lungs in particular, suffer a
great deal during the time they are removed, transported,
and put in to another body." said Steven M.
Albelda, MD, vice chief of the Pulmonary, Allergy,
and Critical Care Division of Penn's Department of Medicine.
"In fact, our findings show that the anti-PECAM/catalase
is most effective when given to the donor prior to organ
removal, as it protects the lung when it is in cold
According to the researchers, the PECAM molecule was
an attractive target because there are a great many
of them on the surface endothelial cells, even during
times of physiological stress. Following transplant,
the researchers were able to determine that the anti-PECAM/catalase
conjugates accumulated in the blood vessels of the lungs
and retained their activity for a prolonged period during
cold storage, transplantation, and the restoration of
"Endothelial cells are particularly vulnerable
to oxidative stress but, unfortunately, most antioxidant
enzymes do not last very long in the bloodstream,"
said Muzykantov. "By combining an antioxidant with
an antibody, we can direct an enzyme to where it needs
to be and keep it there."
According to Muzykantov, their research provides a proof-of-concept
for this method of drug delivery. They are seeking to
further streamline the process by which they can join
the anti-PECAM antibody to the catalase enzyme in order
to make the anti-PECAM/catalase into a more effective
and easily produced therapeutic.
"This immunotargeting approach may be extremely
valuable," said Muzykantov. "It could reduce
injury during clinical lung transplantation and may
dramatically increase the amount of time that lung grafts
are stored, thereby increasing the pool of donor lungs
for use in clinical transplantation. This approach could
also likely be applied to other organ transplants."
Other Penn researchers involved in this paper include
Melpo Christofidou-Solomidou from the Department of
Medicine, and Thomas D. Sweitzer, Donald G. Buerk, and
Silvia Muro from Penn's Institute for Environmental
Medicine. Researchers contributing from other institutions
include Charalambos C. Solomides of Temple University,
and Benjamin D. Kozower and G. Alexander Patterson of
Funding for this research was provided by the National
Institutes of Health and the American Lung Association.
The anti-PECAM antibody was a gift from Dr. Marian Nakada,
Centocor, Inc., of Malvern, Pennsylvania.
# # #
Editor's Note: Drs. Albelda and Muzykantov
do not have a financial stake in Centocor, Inc.
for accompanying illustration.