London-based Immune Targeting Systems Ltd. is developing synthetic peptide-based vaccines against rapidly mutating viruses. The company, which was founded by CEO Carlton Brown and CSO Bertrand Georges in October 2003, uses its antigen identification and fluoropeptide antigen delivery technology platforms to create vaccines designed to stimulate T-cell-based immunity rather than the antibody-based immune responses triggered by most conventional vaccines.
"Most vaccines generate antibodies against viral surface antigens that can mutate, known as antigenic drift and shift, making the vaccines less effective," explains Brown. "Our technology generates T-cell immunity against parts of the virus that do not mutate. The net effect of T-cell immunity is to reduce the impact of viral infection on clinical disease and lessen its severity."
ITS' lead product is a universal influenza vaccine that targets all potential seasonal and pandemic influenza strains, including swine/H1N1 and the highly pathogenic avian H5N1. To create the vaccine, the company used its bioinformatics platform and a variety of laboratory-based methods to identify highly conserved and immunologically relevant influenza antigens from all H1, H2, H3, H5, H7, and H9 influenza-A virus strains known to have infected humans, pigs, and birds. These conserved antigens are packed with CD4 and CD8 epitopes able to generate broadly cross-reactive T-cell responses in all ethnic populations. These selected peptide antigens, 35 amino acids long, are conjugated to fluorocarbon molecules, using Immune Targeting Systems' fluoropeptide delivery system technology. To deal with viral diversity, and with genetic diversity within the human population, the vaccine is made up of a mixture of a number of fluoropeptides. The formulation of fluoropeptides self-assembles into nanoparticles when reconstituted prior to vaccination, and creates a depot on vaccine administration. The company expects the vaccine to trigger robust T-cell immunity with no need for an adjuvant, given the immune responses seen in vivo in multiple animal species.
"We thought about the product profile right from the beginning. Using in-house vaccine design, molecular immunology, chemistry, and manufacturing expertise, we have created a rationally designed vaccine that should have good safety and tolerability. We expect the high density of CD4 and CD8 epitopes to program the immune system to produce the immune response we desire. Because we have included swine and avian antigens, as well as human ones, this is expected to have potential for pandemic as well as seasonal influenza," says Brown.
The researchers began by selecting around 20 conserved sequences meeting the required molecular profile from the influenza virus, and the company worked with an undisclosed manufacturing partner to synthesize the sequences. "We used synthetic sequences, so we would not have to rely on cell lines or hens' eggs for production. We rejected some sequences early on because of manufacturing problems, and others because they were not stable at 40C. By stress testing vaccine antigens at high temperatures we can ascertain long-term storage stability, which is a key requirement for stockpiling of vaccine for pandemic use," explains Brown.
There are a number of bottlenecks in the complex production process of a conventional seasonal influenza vaccine produced in hens' eggs. Chickens are bred to lay eggs for the vaccine production in summer, and the eggs are laid in time to start producing the vaccine when governments and the World Health Organization (WHO) predict the strains of influenza virus that the vaccine must target in January the following year. The process takes around nine to 12 months overall. "The universal nature of our vaccine means we do not need to re-manufacture the vaccine each year within the current manufacturing cycle, or wait for the WHO to identify and sequence a pandemic influenza strain, which takes vaccine manufacturing off the critical path," explains Brown. "We can produce the vaccine out of season and freeze it because the long-term stability data show no loss of purity."
The company's scientists have validated the universal influenza vaccine in in vitro studies using HLA binding assays, and they have shown that T cells raised against the vaccine antigens recognize and kill infected cells. In preclinical animal studies, the universal influenza vaccine shows a potent T-cell response aligned with best-in-class without using adjuvants, according to Brown. "These results give us a lot of confidence. The T-cell response is especially important in disease prevention in the elderly, chronically ill individuals, and young people, which are the populations where conventional vaccines are not as effective as we would like."
With submission of a CTA (clinical trial application) planned for late 2009 for the company's lead product, Immune Targeting Systems expects to begin clinical trials in early 2010, including dose escalation safety and tolerability studies, as well as measurement of immunogenicity. This will be followed up in the second half of 2010 by a Phase IIa human influenza challenge study at a quarantine unit, through a contract research organization.
Brown says the vaccine technology is broadly applicable for a variety of other viral and pathogen infections as well as cancers and is not species dependent. The company has pre-optimized vaccine candidates against hepatitis B, hepatitis C, HIV/AIDS, and FIV (feline immunodeficiency virus, also known as feline AIDS). Development of these will be dependent on funding, and the company may seek partners for non-core programs, such as cancer and some areas of infectious disease.
"In the early years the company focused on HIV, but in late 2005 we decided to take the opportunity to redirect to influenza. The litany of failure in the HIV field made fund-raising impossible and not having sufficient critical mass of proof in the field of HIV meant stakeholders funding HIV vaccine development were not interested in the potential of this platform. Consequently, Immune Targeting Systems switched to the influenza vaccine so we could raise some funding and get the technology moved forward," says Brown. In mid-2007, ITS raised Series A funding. [200730523] The company secured Novartis Venture Funds as its lead investor, and then recruited HealthCap, Truffle Capital, and the London Technology Fund, raising £4.0 million, including a £0.5 million grant from the London Development Agency. Along with an additional £2.4 million provided by the investors in 2009, the resources have been used to fund lead optimization and development of GMP material for preclinical and clinical trials.
"We are currently looking for Series B funding, and expect to finalize this in the third quarter of 2009," says Brown. "As a venture-capital-funded company, our ultimate goal is to obtain resources for the company to develop the programs to the point where they become attractive to a large vaccine company, when we would look to provide an exit for our investors."
According to background competitor research carried out by Immune Targeting Systems, the biotech pipeline includes just over 60 influenza product candidates, with the lion's share of these targeting antigens on the virus surface. "These antigens, including hemagglutinin, neuraminidase, and M2e, are highly variable, and vaccines need to match them specifically to produce a protective response. Without an exact influenza-strain match vaccine efficacy is undermined, making them unsuitable as a first line of defense in a pre-pandemic scenario," says Brown.
A number of companies, including VaxInnate Inc., Juvaris BioTherapeutics Inc., Merck & Co Inc., and Sanofi-Aventis' Acambis PLC, are developing vaccines against M2, which is claimed to be a universal influenza surface antigen, but this is still a variable protein and won't generate a T-cell response relevant for a multi-ethnic human population, according to Brown. BiondVax Pharmaceuticals Ltd. is developing a vaccine designed to elicit both a T-cell and a B-cell response, as is Dynavax Technologies Corp. "We have a unique universal vaccine, which targets all potential seasonal and pandemic influenza strains, is fully synthetic, stable, scalable, and adjuvant-free, and we do not require two different vaccine technologies to generate the desired immune response," says Brown.
Brown originally trained as a veterinary surgeon, but decided to move into the biotech industry in the mid-1990s after concluding his MBA at The London Business School. "I always saw myself running a biotech company, being an entrepreneur and shaping early-stage innovation to develop disruptive technologies. I wanted an adventure and biotech was the new frontier," he says. "Founding Immune Targeting Systems and bringing together a small team of experienced vaccine development scientists with different and relevant backgrounds gave me the opportunity to shape the vaccine technology innovation to specifically address major global disease problems while addressing key vaccine design challenges early on, particularly around manufacturing and formulation development." Since Immune Targeting Systems completed its Series A funding, Brown has built the company up to its current size of seven full-time employees and three part-time employees; he also has created a virtual network of expert advisors and consultants, and added to the existing board of directors and scientific advisory board. "In our team we have pulled together a group of bright minds with a wide range of experience, including drug development and chemistry and manufacturing controls. Bringing in the right people at the right time enables progress, and we have plans to recruit a few more key people to strengthen the management team."
--Suzanne Elvidge
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