Acceleron is developing several other therapies based on this underlying science, including ACE-031 for muscle growth. This
therapy will seek to grow muscle in patients by turning off myostatin, or GDF-8, and holds promise to treat ALS (amyotrophic
lateral sclerosis) and muscular dystrophy. In this category, it will face stiff competition, with Wyeth and Amgen investing
their own research muscle in these promising processes. –JOANNA BREITSTEIN
ANTIBODIES' NEW RIVAL
Adnectins—the fast and mean disease-fighting machine
Monoclonal antibodies and drugs like Avastin and Herceptin have radically changed the treatment landscape. Targeted protein
therapeutics are the fastest-growing segment of the biopharmaceutical market, with $17 billion in sales last year. But as
much as these compounds have advanced the state of care, says Davinder Gill, senior director of biologic therapeutics for
Wyeth Research, there are still some unanswered questions. Asks Gill, "Shouldn't antibodies work better? Cost less? Be easier
to manufacture? I mean, is this the best we can do?"
Today, researchers like Gill are looking into protein-scaffold technologies as a next-generation platform to engineer high-science
drugs. "Think of it like origami," says Gill. "You start with a sheet of paper, but then can fold it in many ways. Each shape
represents a different function. But that piece of paper is like a template that we can use repeatedly to develop drugs against
Of the scaffolds under research, one of the most promising is adnectins. Adnectins, shaped like the part of an antibody that
binds targets, are composed of fibronectin (a human protein that binds to different types of molecular entities). Adnexus
Therapeutics, a privately held 40-person shop based in Waltham, MA, has built its research pipeline on this technology and
is working to engineer amino-acid sequences to target specific medical conditions.
The company recently signed an agreement with Bristol-Myers Squibb to develop their lead oncologic candidate, Angiocept (CT-322),
which is set to enter Phase II trials in late 2007. Angiocept works somewhat like Avastin in that it blocks new blood vessels
from forming and supplying tumors with the nutrients to grow. However, Avastin targets just VEGF-A, while Angiocept targets
VEGF-A, VEGF-C, and VEGF-D, which may heal patients more completely.
Indeed, the ability to bind to multiple targets means that adnectins offer hope in treating more complex diseases. "For 20
years, we've been trying to figure out how to get an antibody to hit more than one target," says Adnexus CEO John Mendlein.
"There are few examples of this because it goes against nature's original design, which is to make an antibody bind to only
The most promising benefits of this scaffold, however, may be commercial, not clinical. Because adnectins are smaller than
antibodies—Gill says they are closer to the "speedboats" of small molecules, compared with the "cruise ships" of large molecules—they
are easier to handle. For instance, Adnexus plans to manufacture the proteins in E. coli, a much cheaper method of manufacturer than the one for Avastin, which is produced in Chinese hamster ovary cells.
The company also sees the potential for rapid screening of possible adnectin candidates. Using a proprietary technology, the
company can generate trillions of versions of a biologic in a single sample, then, in Mendlein's metaphor, "fish" in it using
the target as bait. "It's like a Google search engine for finding a pharmaceutical. We make all these different variations
of adnectin and then find the right one that has the affinity, selectivity, immunogenicity, and manufacturing properties that
we believe will confer an advantage in the marketplace."
Additional protein-scaffold technologies are in the works. They include compounds built on single-domain antibodies, tetranectins,
small modular immunopharmaceuticals, A-domain proteins, ankyrin repeat proteins, and lipocalins. –JOANNA BREITSTEIN
THE 411 ON GLIALS
How does an asthma drug become a medication for neuropathic pain? Alchemy, recycling, or simply smart science?