NATURE: MONOCLONAL ANTIBODIES AND INFLUENZA: Rapid cloning of high-affinity human monoclonal antibodies against influenza virus

[Giuseppe]

Rapid cloning of high-affinity human monoclonal antibodies against influenza virus
May 30 2008, 2.00.00 | Jens Wrammert

Rapid cloning of high-affinity human monoclonal antibodies against influenza virus
Nature 453, 667 (2008). doi:10.1038/nature06890
Authors: Jens Wrammert, Kenneth Smith, Joe Miller, William A. Langley, Kenneth Kokko, Christian Larsen, Nai-Ying Zheng, Israel Mays, Lori Garman, Christina Helms, Judith James, Gillian M. Air, J. Donald Capra, Rafi Ahmed & Patrick C. Wilson

Pre-existing neutralizing antibody provides the first line of defence against pathogens in general.

For influenza virus, annual vaccinations are given to maintain protective levels of antibody against the currently circulating strains.

Here we report that after booster vaccination there was a rapid and robust influenza-specific IgG+ antibody-secreting plasma cell (ASC) response that peaked at approximately day 7 and accounted for up to 6% of peripheral blood B cells.

These ASCs could be distinguished from influenza-specific IgG+ memory B cells that peaked 14?21 days after vaccination and averaged 1% of all B cells.

Importantly, as much as 80% of ASCs purified at the peak of the response were influenza specific.

This ASC response was characterized by a highly restricted B-cell receptor (BCR) repertoire that in some donors was dominated by only a few B-cell clones.

This pauci-clonal response, however, showed extensive intraclonal diversification from accumulated somatic mutations.

We used the immunoglobulin variable regions isolated from sorted single ASCs to produce over 50 human monoclonal antibodies (mAbs) that bound to the three influenza vaccine strains with high affinity.

This strategy demonstrates that we can generate multiple high-affinity mAbs from humans within a month after vaccination.

The panel of influenza-virus-specific human mAbs allowed us to address the issue of original antigenic sin (OAS): the phenomenon where the induced antibody shows higher affinity to a previously encountered influenza virus strain compared with the virus strain present in the vaccine.

However, we found that most of the influenza-virus-specific mAbs showed the highest affinity for the current vaccine strain.

Thus, OAS does not seem to be a common occurrence in normal, healthy adults receiving influenza vaccination.
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Re: _|NATURE: MONOCLONAL ANTIBODIES AND INFLUENZA|_

Re: _|NATURE: MONOCLONAL ANTIBODIES AND INFLUENZA|_

Crucell Announces Excellent Results for Influenza Antibody

Marketwire - Dec. 11, 2008
http://www.therapeuticsdaily.com/ne...ntryarticle&contentvalue=1872474&channelID=31

LEIDEN, NETHERLANDS,/ MARKET WIRE/
Dutch biopharmaceutical company Crucell N.V. (Euronext, NASDAQ: CRXL) (SWISS: CRX) today announced that its monoclonal antibody (mAb) directed against a broad range of influenza virus strains has strongly outperformed the most current anti-influenza drug in preclinical tests.

The latest results were presented yesterday, by Dr Jaap Goudsmit, at IBC's 19th Annual International Conference on Antibody Engineering in San Diego, USA. The preclinical study compared Crucell's mAb CR6261 with the anti-influenza drug oseltamivir in terms of their value for flu prevention and treatment.

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. Dr Goudsmit 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 for the prevention and treatment of H1N1 infection, illustrating the potential use for seasonal applications as well.

This makes it a potentially powerful antibody against a broad range of influenza strains. Fears of a flu pandemic are fuelled by the rising number of flu strains that have mutated in ways that make them resistant to oseltamivir.

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 advantages of the mAb over oseltamivir may also be important for protecting or treating people at risk of severe illness or death due to seasonal flu. These include the elderly and immune-suppressed individuals.

The characterization of the antibody will be described in the online journal PLoS ONE (www.plos.org) on December 16, 2008.

"An effective treatment of influenza is urgently needed.
The limited efficacy of oseltamivir and the rising resistance to this anti-influenza drug are cause for concern.
I am very encouraged by these preclinical results indicating that our monoclonal antibody may provide an effective means for disease prevention and cure," said Jaap Goudsmit, Crucell's Chief Scientific Officer.

"Although this antibody is still at any early stage of development, these results are very promising and demonstrate the strength of our in-house research and development aimed at bringing innovation to global health," said Ronald Brus, Crucell's Chief Executive Officer.

http://www.therapeuticsdaily.com/ne...ntryarticle&contentvalue=1872474&channelID=31

 

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Re: NATURE: MONOCLONAL ANTIBODIES AND INFLUENZA: Rapid cloning of high-affinity human monoclonal antibodies against influenza virus

Letter abstract

Nature Medicine 14, 1357 - 1362 (2008)
Published online: 23 November 2008 | doi:10.1038/nm.1885

Targeting inside-out phosphatidylserine as a therapeutic strategy for viral diseases

M Melina Soares1, Steven W King2 & Philip E Thorpe1

There is a pressing need for antiviral agents that are effective against multiple classes of viruses. Broad specificity might be achieved by targeting phospholipids that are widely expressed on infected host cells or viral envelopes. We reasoned that events occurring during virus replication (for example, cell activation or preapoptotic changes) would trigger the exposure of normally intracellular anionic phospholipids on the outer surface of virus-infected cells. A chimeric antibody, bavituximab, was used to identify and target the exposed anionic phospholipids. Infection of cells with Pichinde virus (a model for Lassa fever virus, a potential bioterrorism agent) led to the exposure of anionic phospholipids. Bavituximab treatment cured overt disease in guinea pigs lethally infected with Pichinde virus. Direct clearance of infectious virus from the blood and antibody-dependent cellular cytotoxicity of virus-infected cells seemed to be the major antiviral mechanisms. Combination therapy with bavituximab and ribavirin was more effective than either drug alone. Bavituximab also bound to cells infected with multiple other viruses and rescued mice with lethal mouse cytomegalovirus infections. Targeting exposed anionic phospholipids with bavituximab seems to be safe and effective. Our study demonstrates that anionic phospholipids on infected host cells and virions may provide a new target for the generation of antiviral agents.
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1. Department of Pharmacology, 6001 Forest Park Road, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041, USA.
2. Peregrine Pharmaceuticals Inc., 14272 Franklin Avenue, Tustin, California 92780, USA.

Correspondence to: Philip E Thorpe1 e-mail: Philip.Thorpe@UTSouthwestern.edu

http://www.nature.com/nm/journal/v14/n12/abs/nm.1885.html