Some of the most successful biotech drugs ever created are designed to hit just one specific target on diseased cells, while sparing all sorts of markers found on healthy cells. But if Biogen Idec scientist Tony Manning and his colleagues are right, antibodies that specifically hit two targets could someday be better than one.
Cambridge, MA-based Biogen Idec (NASDAQ: BIIB) has long been a leader among companies that make monoclonal antibodies, which are made to specifically home in on a single specific target found on diseased cells. This is the mode of action behind one of Roche and Biogen’s classic hits, rituximab (Rituxan). Other biotech drugs, including products from Cambridge, MA-based Genzyme, are engineered proteins that replace something essential in the body. Still others like those from Amgen stimulate production of essential red and white blood cells.
But if your goal is to hit a specific target on diseased cells and you believe that say, certain autoimmune diseases and cancers are really complicated and involve cells with many different markers of disease, then wouldn’t it make sense to see if a drug can specifically block two targets? Essentially, as the old cliché goes, wouldn’t that be like killing two birds with one stone?
That’s how Manning sees it.
“These are next-generation biotherapeutics that could transform the business of biotech products,” says Manning, Biogen’s vice president of inflammation and autoimmune disease research.
Rituximab was approved by the FDA as the first monoclonal antibody for cancer back in 1997, and that opened the floodgates for an antibody boom. Biotech companies are estimated to rake in more than $30 billion in sales next year from these little Y-shaped proteins that treat all kinds of diseases like non-Hodgkin’s lymphoma, lung cancer, rheumatoid arthritis, and multiple sclerosis.
Ever since genetically engineered antibodies were first synthesized in the 1970s, scientists have sought ways to make them better. Earlier this week, I described how Waltham, MA-based ImmunoGen (NASDAQ: IMGN) is working with Roche on what those companies hope will be the first commercially successful drug that attaches an antibody to an extra-potent toxin.
Taking a different approach, Manning spearheads a group at Biogen who dream of engineering a new class of antibodies that can hit two disease targets on cells, not just one. These are so-called “bispecific” antibodies. This is all at a very early stage of research, and none of these drug candidates have yet advanced into clinical trials, but to hear Manning talk, they will be a big deal someday not too far in the future.
The potential advantages of such a two-pronged antibody are pretty clear. Take rheumatoid arthritis, for example. Researchers know that drugs that block targets on cells called TNF and IL-6 can be effective at dampening the excess inflammation in the disease. It could be hypothesized that giving both types of drugs together might increase overall effectiveness, but that would also add a number of injections that patients might not want, and the two drugs could increase side effects if they are given at the same time, Manning says.
So Biogen scientists have been working on a way to fuse together an antibody that can recognize two targets at once. This bispecific antibody doesn’t look like a classic Y-shaped antibody, but rather, more like an X-shaped double antibody that recognizes a different target on each end. Without getting too technical, this is basically easier said than done. “It’s a molecular biology challenge,” Manning says. “People have been working on this for 25 years.”
Many other companies have tried this, without any big commercial success. Manning handed me a review article published in the journal Pathobiology in 2007 that has a handy chart listing drug candidates from Micromet, MedImmune, Trion Pharma, Fresenius Biotech, and Medarex. Many past efforts have been hampered by laborious production procedures, according to the Nicolas Fischer and Olivier Leger of Switzerland-based NovImmune, who wrote that review.
One of the keys to getting this right is making the new bispecific antibodies stable, and practical to scale up in consistent, large-scale commercial batches, Manning says. This is one step where companies often fall down, because of a lack of communication from the basic researchers and biotech drug manufacturing experts, but Manning insists that at Biogen those two groups are on the same page. If anything, Manning says, the manufacturing group is “more enthusiastic” than the science group he heads.
How far along has this work progressed? Biogen has selected two leading candidates for clinical trials, and expects to push them into human tests in 18 to 24 months, Manning says. When I pressed him for details about these drugs, he started getting more tight-lipped.
But I was able to gather some tidbits. The first bispecific antibody candidate is being developed for an immunologic disease by blocking one “well-validated target” plus a second target that’s novel to Biogen, Manning says.
The next product candidate is for cancer, Manning says. Biogen is hopeful about this drug because it essentially has two ways of more effectively shutting down the insulin-like growth factor receptor. Biogen already has a more traditional antibody against this target in clinical trials, as does Pfizer, but neither one of them causes the complete blockade of the target that the bispecific antibody does in lab experiments, Manning says. That’s important because partial blockage of the target is thought to be one reason tumors often find ways to resist new targeted treatments over time, Manning says.
Of course, a huge amount of work will have to be done to show these drugs are safe. Drugs that block TNF and IL-6 independently are already associated with making patients vulnerable to infection, and the FDA will surely watch for any sign that a bi-specific antibody makes patients any more susceptible.
But if Biogen has success with its first two bispecific antibody candidates, there will be some strong lobbying within the company to develop more of these kinds of drugs. They may not ever completely replace the original monoclonal antibodies like rituximab, but they could eventually be on an even footing, Manning says. “Our goal is to have half of all biologics move to this platform,” he says.
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