Human Antibodies against a broad range of Influenza

Crucell has discovered the first human monoclonal antibodies for the prevention and treatment of the 'bird flu' strain H5N1, as well as H1N1, which is similar to the strain responsible for the 'Spanish flu' in 1918. The antibodies provide immediate protection and neutralize a broad range of H5N1 and H1N1 strains in pre-clinical models. In December 2008, Crucell presented data showing that the mAb CR6261 was 100% successful in preventing infection with H5N1. When given after H5N1 infection, Crucell's mAb demonstrated the ability to prevent death and cure disease in all cases. The mAb also performed significantly better than the anti-influenza drug oseltamivir for the prevention and treatment of H1N1 infection, illustrating the potential use for seasonal applications as well. This is especially important as the resistance of influenza strains for oseltamivir is rapidly increasing.

In December 2008 Crucell announced that its monoclonal antibody had strongly outperformed the most current anti-influenza drug in these tests. The results were presented at IBC's 19th Annual International Conference on Antibody Engineering in San Diego, USA.

The flu strains tested included the 'bird flu' strain H5N1, which, experts fear, has the potential to cause a pandemic, and H1N1, which is similar to the strain responsible for the devastating pandemic in 1918.

Importantly, the study showed that CR6261 provides immediate protection against the influenza virus, suggesting that it will be able to prevent disease spread. In contrast, oseltamivir was less efficacious and in some cases not effective at all. The characterization of the antibody was described in the online journal PLoS ONE on December 16, 2008.

On August 18^th, 2009 Crucell announced that it received a National Institute of Allergy and Infectious Diseases (NIAID)/National Institutes of Health (NIH) contract aimed at advancing the development of monoclonal antibodies for the treatment of seasonal and pandemic influenza. The contract provides funding of up to $40.7 million, with additional options that may be triggered at the discretion of the NIH worth a further $28.4 million, bringing the potential total amount to $69.1 million. This project has been funded in whole or in part with Federal funds from the National Institute of Allergy andInfectious Diseases, National Institutes of Health, Department of Health and Human Services, under ContractNo. HHSN272200900014C.

Development Rationale

There is a growing fear within the medical community concerning the potential re-occurance of a pandemic influenza outbreak, similar to the 1918 “Spanish flu” pandemic. A pandemic can start when a new influenza virus subtype emerges that meets three conditions: it infects humans causing serious illness; it spreads easily; and there is sustained human-to-human transmission of the virus. The H5N1 virus meets the first two conditions, and the risk that the virus acquires the third ability will persist as long as opportunities for human infections occur.

Crucell has discovered a total of twenty-one human monoclonal antibodies that have been found to neutralize the avian influenza H5N1 virus. The set of monoclonal antibodies, which was produced by Crucell researchers using phage display and Crucell PER.C6® technology, showed the potential to neutralize the broadest range of H5N1 viruses including A/Vietnam/11994/04, A/Hong Kong/213/03 and A/Hong Kong/156/97. The antibodies apparently recognize a part of the viral membrane protein that is present among all H5N1 viruses tested. The most potent neutralizing antibody was tested in pre-clinical models for the ability to protect against infection with the highly pathogenic A/Hong Kong/97 H5N1 virus and was also tested for its ability to stop the development of the disease caused by this virus. When the monoclonal antibody was given in a pre-clinical model, one day prior to infection with the H5N1 virus, it resulted in full protection against infection. Treatment with the antibody up to three days after infection resulted in 100% survival and cure of the disease. This antibody may therefore provide a powerful tool in pandemic preparedness.

About Influenza

Influenza, commonly known as 'flu', affects large sections of the world's population each year. The disease is characterized by annual winter outbreaks, which often reach epidemic proportions due to the fact that the virus can mutate quickly, often producing new strains against which human beings do not have immunity. Typical symptoms of flu are usually relatively mild but can become life threatening in vulnerable patient groups, such as the elderly and immunodeficient individuals. In a growing number of countries, small children have been added to the list of preferred protection groups. Transmission of the flu virus occurs through airborne particles and upon infection, the incubation period ranges from one to three days.

Each year approximately 5%-15% of the world's population contracts influenza and an estimated 250,000 to 500,000 people die annually from influenza-associated complications according to the World Health Organization. As well as these annual epidemics, a major genetic shift in the influenza virus can occasionally lead to a deadly new virus strain to which the human population does not have immunity, resulting in a global pandemic.

An influenza pandemic is a rare but recurrent event. Three pandemics occurred in the previous century: 'Spanish influenza' in 1918, 'Asian influenza' in 1957, and 'Hong Kong influenza' in 1968. The 1918 pandemic caused an estimated 40 to 50 million deaths worldwide. That pandemic, which was exceptional, is considered one of the deadliest disease events in human history. Subsequent pandemics were much milder, with an estimated 2 million deaths in 1957 and 1 million deaths in 1968.