December 1, 2009 (Vol. 29, No. 21)

Pipeline Gap Could Be Remedied by Recent Innovations and Fruitful Biotechnology Partnerships

Big pharma faces a patent cliff in 2012 when around $90 billion in revenue could be lost to generics. The companies that are going to weather this storm have to look at other revenue streams. Vaccine development is gaining a lot of attention because it has an attractive adjacency to many pharmaceutical companies’ existing R&D, manufacturing capacity, regulatory expertise, and customer base.

Additionally, producing vaccines is the kind of activity that lends itself well to collaborative partnerships, explained Franz-Robert Klingan, Ph.D., partner at Bain & Company, at the recent “World Vaccine Congress” in Lyon.

Traditionally, several major pharmas have been heavily invested in vaccine production including sanofi-aventis, GlaxoSmithKline, Merck and Wyeth (now part of Pfizer). Novartis became a major producer with the acquisition of Chiron in 2006. Many factors are persuading other big players to enter the vaccine fray with gusto, including the lack of corresponding vaccines for over 40 different pathologies and the significant potential of therapeutic vaccines.

“Three years ago we were not viewed as being in the vaccine business,” Rob Sinclair, director of worldwide business development at Pfizer, said. “We’re catching up now as a result of the acquisition of PowderMed in 2006 and Coley Pharmaceuticals in 2007. We now have access to DNA vaccine technology and a TLR9 adjuvant. We also licensed CDX-110, an immunotherapy to treat malignant glioblastoma, from Celldex Therapeutics in 2008 and virus-like particle technology from Cytos this year.”

The vaccine market is also proving attractive to biotechs because the development cycle for vaccines is often much shorter than for therapeutics. “Biotechs can contribute innovation that pharmas need,” explained Katherine Cohen, Ph.D., svp, global head corporate and business development at Intercell. “In the beginning, big pharma controlled the value chain. Now biotechs can keep it for as long as possible and even bring vaccines to market as we have done this year with our Japanese Encephalitis vaccine.”

On Target for Success

Many biotechs at the “World Vaccine Congress” had plenty of innovation to shout about, including Vaccibody. This spin-out from the University of Oslo showed off a twist on antibody technology that helps target vaccines to boost T-cell immunity.

“A vaccibody construct is a three-component antibody-like molecule,” Dr. Ole Henrik Brekke, Ph.D., CEO of Vaccibody, said. “It has a targeting unit that can be part of an antibody or binding ligand that attaches to surface molecules on antigen presenting cells (APC). The targeting unit is attached to a dimerization unit consisting of a hinge and CH3 domain from an immunoglobulin, so this section of the vaccibody even looks a bit like an antibody. Finally, the third part is the antigen or the vaccine unit.”

“Vaccibodies work by binding surface molecules on APCs,” Dr. Brekke continued. “The complex is taken up, and antigenic peptides are presented to CD4 or CD8 cells. The CD4 T cells secrete cytokines that help B cells develop into plasma cells that secrete huge amounts of antibodies. The CD8 and CD4 T cells as well as the antibodies generated eliminate the infectious agent or tumor cells they have been targeted against.”

To demonstrate proof of this concept, the company produced two types of vaccibodies containing pandemic flu and seasonal flu antigens. One is a normal targeting vaccibody and the other version has a mutation in the targeting unit so that it will not bind to APCs.

Dr. Brekke presented mouse model data that showed 100 days after vaccination, the targeted vaccibody generated IgG levels five times higher than the nontargeting vaccibody. The CD8 and CD4 levels measured by ELISPOT were five to eight times higher (respectively) than the nontargeted vaccibody, showing that targeting the vaccibody does promote T-cell immunity.

Additionally, 14 days after vaccination the mice injected with a vaccibody and challenged with a flu virus did not lose body weight compared to the unimmunized mice. The unimmunized mice showed drastically reduced weight and had to be sacrificed nine days after they were infected.

“As long as you know the gene sequence of the antigen you can easily exchange the vaccine unit so this type of vaccibody platform could be used to produce prophylactic or therapeutic vaccines against a range of diseases,” Dr. Brekke stated. “Vaccibody technology offers good safety, stability, and efficacy. Now that we have preclinical proof the vaccibodies work well we are seeking partners that would like to license this technology.”

A vaccibody is a three-component antibody-like molecule. (Vaccibody)

Two interesting and very different technologies for vaccine delivery were presented by Mucosis and Hybrid Systems.

“We have developed a new way of formulating Lactococcus lactis into nonviable cells that can be loaded with antigens. We call these GEM (gram-positive enhancer matrix) particles, and when these are sprayed into the nose they raise protective immunity by activating the innate and adaptive immune system,” said Govert Schouten, Ph.D., CEO at Mucosis.

Using this platform, Mucosis has produced FluGEM™, an intranasal vaccine containing a range of flu antigens. Dr. Schouten presented preclinical data to show that of the 24 mice challenged with H3N2 flu virus, all 12 mice immunized with a FluGEM vaccine intranasally survived, while only two survived in the control group of 12 dosed with phosphate buffered saline.

“Needle-free intranasal application with this technology is possible and could be used to develop a universal flu vaccine,” Dr. Schouten stated. With FluGEM we are now moving into ferret models. We hope to begin Phase I trials soon.”

According to Mucosis, its FluGEM vaccine adds an additional layer of protection to boost influenza vaccine efficacy.

Hybrid Systems, on the other hand, offers a vaccine delivery system aimed at use with viral vectors. “We use polymers to coat viruses. This makes a stealth virus that can hide from the immune system so that it can deliver its DNA vaccine safely without being recognized and destroyed by antibodies,” explained John Beadle, M.D., executive chairman and CEO at Hybrid.

As proof of this, Dr. Beadle showed several examples where viruses coated with the polySTAR polymer used in small rodent studies appeared to evade the immune system and increase proliferation of T cells. In one, an Ad5 OVA with and without a coat polymer containing a lipid dipalmitoyl-S-glyceryl cysteine (Pam2Cys) were injected into mice. The mice produced double the number of CD8 T cells with the coated virus.

In another study, a vaccine consisting of recombinant vaccinia virus encoding the tumor-associated antigen carcinoembryonic antigen (CEA) was coated with the polymer and injected into mice. The number of CD4 cells was almost doubled in those mice injected with the coated virus and even in mice that had been preimmunized with vaccinia-CEA vaccine the CD4 response increased more than sixfold that of the uncoated virus.

“This process sounds complicated, but is very simple as you just have to co-incubate the polymer with the virus and the polymer will coat the virus according to size and charge density,” Dr. Beadle stated. “Therefore, this process could be carried out in a GMP environment. It can be used with any virus that does not have a friable envelope, so is applicable to MVA, AAV, Herpes, and Adeno viruses. We think its primary use will be to deliver prime and boost DNA vaccinations, but it could also be used to deliver gene therapy vectors.”

Hybrid System’s polySTAR-coated adenovirus has a 20% larger diameter than the unmodified virus.

Where’s the Profit?

With biotechs in the vanguard of developing some interesting platform technologies and even novel vaccines, some companies are taking their products all the way to market but they need to exercise caution when doing this. “When biotechs are developing vaccines, manufacturing is often the last thing on their mind, yet improving output is often the differentiator between making a good profit or very little return on a product,” warned Catarina Flyborg, leader of enterprise solutions at GE Healthcare.

To prove this point, Flyborg presented examples where using a range of ready-to use products such as bioreactors, pre-packed chromatography columns, and filters could significantly increase the number of doses, while reducing cost of goods.

According to Flyborg, 500 L Wave disposable bioreactors could be used to produce 18 batches of a trivalent flu vaccine. This would total six batches per strain producing four million doses and could be made in 90 days by applying ready-to-use systems, in a staggered production mode. She added that to produce the same number of doses using a traditional set up of stainless steel fermentors, repacking and cleaning chromatography columns, would take 96 days.

“Companies can apply ready-to-use technology and rapidly put together a facility that suits their needs. However, once you get past the 10,000 L scale using ready-to-use and disposable technology, the cost of goods becomes so high that this is not a workable option, so it really benefits small biotechs that don’t have existing capacity, or companies looking to quickly set up and produce batches in countries where they don’t have facilities.”

According to Dr. Klingan, in 1992 the vaccine market was worth €2 billion ($2.96 billion), €15 billion ($22.24 billion) in 2008, and could be worth €33 billion ($48.94 billion) by 2018. The clear way for big pharma to get a slice of this is to develop joint ventures and alliances and in some cases acquire biotech partners to gain technologies or market access. New vaccines require a complex mix of novel technologies and manufacturing capacity, as well as a balanced presence in different geographies if they are going to be sustainably profitable. 

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