* Roche/Genentech discovery opens "new frontier"
* Animal studies show antibody clears Alzheimer's protein
By Julie Steenhuysen
CHICAGO, May 25 Scientists at Roche Holding
AG's ROG.VX biotechnology unit Genentech have found a way to
get antibody-based therapies across a key barrier in the brain
and deliver a payload of drugs that take aim at an elusive
They said the findings from two studies, reported on
Wednesday in the journal Science Translational Medicine, could
open the door to new treatments for diseases like Alzheimer's,
schizophrenia, Parkinson's and even autism.
"This really opens a whole new frontier for antibody
therapies," said Mark Dennis, a senior antibody scientist at
California-based Genentech, a company known for its
antibody-based treatments for cancer.
"Before, the brain was considered off limits," Dennis said
in a telephone interview.
He and colleagues discovered a reliable way of getting
antibody drugs across the blood-brain barrier, a protective
fortress that only allows select molecules or nutrients from
the bloodstream to enter the brain.
"It's protecting the brain from toxins," Ryan Watts,
associate director of neuroscience at Genentech who worked on
both studies, said in a telephone interview.
Small molecules, including some pills, can cross this
barrier, but large molecules, such as engineered antibodies,
get stuck in the tight mesh of cells that line blood vessels in
Companies are already developing Alzheimer's drugs that use
antibodies to attack the Alzheimer's-related protein beta
amyloid, but the problem is that only small amounts can get
into the brain.
Watts estimates less than 0.1 percent make it across.
"This technology significantly improves that," he said.
The discovery came through studies of a new targeted
antibody drug for Alzheimer's disease that works by blocking
beta-secretase 1 or BACE, an enzyme required for chopping up
amyloid beta proteins that go on to form sticky plaques in the
brains of Alzheimer's patients.
Studies in mice and monkeys showed the engineered antibody
effectively reduced the amount of amyloid beta in the animals'
blood, but it had only a modest effect at reducing levels of
the protein in the brain.
To overcome this, the team decided to use a Trojan horse
approach. They knew that iron crosses easily into the brain, so
they made the antibody specifically target transferrin
receptors, which transport iron across the blood brain
But the large molecules kept getting stuck on the receptors
and couldn't make it across the blood brain barrier.
Watts likens it to a ski lift: The molecules got on the
lift, but never got off.
To overcome this, Dennis figured out a way to make the
antibodies less sticky -- by reducing their affinity for the
That allowed enough of the antibodies to fall off the
receptors and enter the brain.
Tests in mice show the antibodies hit their target, and
significantly reduced levels of amyloid beta in the brain.
Several companies, including Eli Lilly and Co (LLY.N), have
been working to develop drugs that target BACE, which is
thought to be a safer target than gamma-secretase.
Lilly pulled the plug on late-stage studies of its
gamma-secretase drug semagacestat last summer because some
people saw declines in brain function, and some developed a
form of skin cancer.
Watts said their beta-secretase 1 antibody is very
specific, and it may prove to be safer, but the big discovery
for him is getting antibodies into the brain.
"We're going after this very aggressively," Watts said,
adding that the company wants to study antibody treatments for
neurodegenerative diseases other than Alzheimer's.
"The list is quite long," Watts said.
(Editing by Gerald E. McCormick)