Bioworld Today Columnist

A few years back, Kirsten Drejer, director of Novo Nordisk's diabetes discovery research, got a call from a former co-worker inviting her to join a group of ex-Novo folks who were looking for an entrepreneurial opportunity. They had a team and an interest in fully human antibodies as therapeutics.

At the 2000 Annual BIO conference in Boston, Drejer heard Jacqueline Sharon of Boston University talk about generating recombinant human polyclonal antibodies (PAbs) against infectious diseases. That sounded like an entrepreneurial science to go with that team. But wait, you say, isn't monoclonal (MAb) the way to go - a highly selective, specific antibody molecule aimed at a single spot on a single antigen?

It's starting to look increasingly that antibody therapy is like many other areas of biology - the more selective and specific the treatment gets, the further you get from the desired in vivo effect.

The immune system spent billions of years evolving an approach that is decidedly NOT aimed at a single antigen, but rather at hitting lots of the identifying bits of bacteria, virally infected cells and cancer cells to mount a multi-pronged attack on the invading "bad guy."

Drejer's interest was driven by her experience at Novo. Her team cooked up lots of insulin analogues, tweaking the protein to look for versions with better pharmacological properties. The team found that the natural insulin molecule was hands-down the best therapeutic. While some of the variants stuck to the insulin receptor better, they also tended to stimulate cell proliferation and cause cancer, which is generally frowned upon by the FDA. "You have to be really careful about changing how nature designs things," Drejer said, "or you learn a lot about unintended consequences."

There are plasma-derived polyclonal products on the market, but they have been limited by production cost, variation from batch to batch and concerns about blood-borne diseases. The recent sexiness of antibody therapies has big biopharma searching around for ways to circumvent those problems. F. Hoffman-LaRoche Ltd. just bought Therapeutic Human Polyclonals Inc., a California company with transgenic rabbits intended to produce human MAbs and pAbs, for $56.5 million.

Sometimes More Is Better

In the summer of 2000, Symphogen was founded in Copenhagen, Denmark, to discover and manufacture polyclonal and MAbs aimed at infectious diseases and cancer. Those diseases present very complex targets - rapidly evolving organisms and cells changing their appearance and structures to hide from monoclonal antibodies and targeted therapies.

That rapid evolution is why we need new flu vaccines on a regular basis, why cancers escape from previously effective chemo and how HIV keeps coming back after each new drug therapy. Symphogen's team believes that striking at multiple targets simultaneously will make it tougher for them to escape and mutate. There is support for this natural approach. The company has raised $85 million from a global group of investors and has 80 people working on six development programs. Meiji Seika and BioVitrum have signed on to partner with Symphogen, and the NIH coughed up a $4.6 million grant for an infectious disease biodefense program.

Big Discovery Advantage

Antibody molecules have a very complex genetic origin, with millions of possible gene combinations going into the final output. How can Symphogen come up with a finite number of antibodies that are likely to have therapeutic value?

By letting natural immune evolution figure out the important antibodies to get the job done.

The Symplex platform technology uses naturally occurring antibody-producing B cells from naturally immune humans as the source of antibody genes. (This is starting to sound like an organic diary.) Unlike many of the competing antibody companies, Symphogen's approach does not require use of other folks' patented technologies, like hybridoma, phage display or directed evolution. Saves big bucks on royalties down the road.

Symphogen's polyclonal approach means that its products are made by several cell lines at the same time, and in controlled proportions. Otherwise, every batch would be different, making regulatory agencies cranky. One of the biggest challenges was getting all the different cell lines, each producing its own antibody molecule, to divide at similar rates. Faster growing lines wanted to take over the combined fermentation vat, which would throw off the proportions of the various antibodies.

Symphogen's lead product candidate, Sym001, contains 25 different IgG1 antibodies aimed at the Rh blood antigen. Mothers lacking Rh factor on their blood cells can make anti-Rh antibodies after delivering an Rh+ baby. In a second Rh+ pregnancy, the maternal immune system attacks and destroys fetal red cells. Moms currently are treated with antibodies from blood donors. Between scarcity of donors and safety concerns over blood-borne diseases, the company and its partner, BioVitrum, saw an opportunity to create a safe, unlimited supply of Rh-blocking treatments.

Symphogen scientists showed that via site-specific integration into the same genomic site in all the cell lines, they could reproducibly generate batches of Sym001 with the same yield, composition, binding potency and functional activity. A Phase I study began in March.

Other Programs

Sym002 uses recombinant pAbs to sop up vaccinia virus to block the adverse effects of current smallpox vaccination - there have been reports of rare, but serious, problems in families of Iraq-bound soldiers in the U.S. and UK. Symphogen plans to use government grants or a partner to develop that. Sym003 is aimed at respiratory syncytial virus, which causes 90,000 hospitalizations in the U.S. and almost 5,000 deaths. RSV in preemies is treated with a humanized mouse-derived monoclonal antibody, Synagis (MedImmune), with worldwide sales of $1.1 billion in 2006. MedImmune's second generation product, Numax, looked good in Phase III trials but is still a humanized product - not fully human. Symphogen is looking for a development partner for the RSV product candidate.

Meiji Seika Kaisha Ltd. struck a deal late last year to work with Symphogen on an undisclosed bacterial pathogen, and the company has some cancer programs in discovery.

With antibody-based therapies growing in favor, Symphogen and its partners should have interesting times ahead as its candidates move through the clinic.

Robbins-Roth, PhD, founding partner of BioVenture Consultants, can be reached at biogodess@earthlink.net. Her opinions do not necessarily reflect those of BioWorld Today.

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