Beursonline.nl

flosz 21 maart 2009 11:23

6

Confirmation of Bogoch Replikins Influenza Patents By Harvard-CDC and Scripps-Crucell Data (March 20, 2009)

Boston, March 20, 2009. Replikins, Ltd. announced today that data recently published from Harvard-CDC and Scripps-Crucell in Nature1 and Science2 confirms the 2001 discoveries by Dr. Samuel and Elenore Bogoch of peptides in the hemagglutinin unit of influenza, which they named Replikins, which are shared across flu strains, conserved over time, associated with the last three pandemics of 1918, 1957 and 1968, as well as current H5N1 outbreaks, and are the basis of broad spectrum flu vaccines. The Replikins sequences, as specified by the Bogoches, are the subject of granted patents from 2001 and a 2005 monograph3.
The amino acid contact points between the neutralizing antibody and the virus that the Harvard-CDC and Scripps-Crucell investigators both observed, out of over 500 possible sites, are in the influenza Replikins. The confirming groups' data also verified the Bogoch 2001 findings of conservation of these very Replikins peptides over decades, and the sharing of Replikins between strains of influenza, making general flu vaccines possible for the first time.
The Replikins peptides, associated with rapid replication, are quantitatively trackable and predictive of the intensity, timing, and country of outbreak. The company's FluForecast® software has correctly predicted recent H5N1 outbreaks and the countries in which they were going to occur.4
Replikins, which are quantitatively related to lethality in influenza and other infectious diseases, such as HIV, anthrax, and malaria, as well as cancer, and a range of animal diseases, are the subject of synthetic vaccines in development at the Company.
1. Sui, J. et al. "Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses.", Nature Structural and Molecular Biology, published online:22 February,2009, doi:10.1038-nsmb.1566.
2. Ekeirt, D.C. et al, "Antibody Recognition of a Highly Conserved Influenza Virus Epitope", Science DOI: 10.1126-science.1171491, Science Published online, Feb. 26 2009
3. Bogoch S. and Bogoch, E.S. Replikins, the Chemistry of Rapid Replication. With examples in influenza, HIV, AIDS, SARS, Malaria, and Cancer. Begell House,Inc. New York, Wallingford, U.K. ISBN 1-56700-200-5, 2005.
4. On-line: see 'Replikins Press', 2006 - 2008. (Press release #12 Indonesia Reports Experiencing Human H5N1 Mortality Increase, as Predicted Last Year by Replikins' FluForecast® Quantitative Virus Analysis (June 8, 2007)

REPLIKINS, Ltd. 38 the Fenway, Boston, MA 02215.
Contact: jjosephson@replikins.com
www.replikins.com/release.html#article25

maxen 21 maart 2009 14:50

4

quote:
flosz schreef:
Confirmation of Bogoch Replikins Influenza Patents By Harvard-CDC and Scripps-Crucell Data (March 20, 2009)

Boston, March 20, 2009. Replikins, Ltd. announced today that data recently published from Harvard-CDC and Scripps-Crucell in Nature1 and Science2 confirms the 2001 discoveries by Dr. Samuel and Elenore Bogoch of peptides in the hemagglutinin unit of influenza, which they named Replikins, which are shared across flu strains, conserved over time, associated with the last three pandemics of 1918, 1957 and 1968, as well as current H5N1 outbreaks, and are the basis of broad spectrum flu vaccines. The Replikins sequences, as specified by the Bogoches, are the subject of granted patents from 2001 and a 2005 monograph3.
...

Vrij vertaald: De onderzoekers van Crucell en Harvard hebben nu, in 2009, bevestigd wat wij, de Bogochjes van de firma Replikins, al in 2001 hebben ontdekt: de universele plekken van de verschillende griepvirussen, die nauwelijks veranderen, en bij al die griepvirussen hetzelfde zijn. Waarop vervolgens universele antibodies op te maken zijn. Wij hadden ze al "replikins" genoemd. En we hebben de patenten er al op.

gogogoo 21 maart 2009 18:55

0

quote:
flosz schreef:
Confirmation of Bogoch Replikins Influenza Patents By Harvard-CDC and Scripps-Crucell Data (March 20, 2009)

AB. Clever boys and Girls.

flosz 23 maart 2009 12:15

3

Het universele griepvaccin
Nieuwe antistoffen pakken virussen bij de wortels aan

Eén prik die beschermt tegen alle mogelijke griepvirussen, kan dat? Het lijkt er ineens wel op. Twee groepen onderzoekers hebben onafhankelijk van elkaar dezelfde truc gevonden om de virussen de voet dwars te zetten.
De dreigende taal van een paar jaar geleden hoor je niet vaak meer, maar het gevaar van een wereldwijde slachting door een nieuw griepvirus bestaat nog steeds. Hoe de dader er precies uit zal zien, dat kunnen virologen niet voorspellen. En dus proberen ze een wapen te vinden dat álle griepvirussen aankan.
Antistoffen die korte metten maken met iedere denkbare griepvariant hebben ze niet, schrijven twee groepen onderzoekers deze week in de wetenschappelijke tijdschriften Nature Structural & Molecular Biology en Science. Maar het scheelt toch niet veel. Ze hebben, onafhankelijk van elkaar, menselijke antistoffen ontdekt die meerdere gevaarlijke griepvirussen herkennen.
Onder die virussen waren twee echte killers: de veroorzaker van de vogelgriep die de afgelopen jaren in Azië honderden mensenlevens eiste, en het virus achter de Spaanse griep, die in 1918 en 1919 minstens vijftig miljoen mensen fataal werd. Bij mensen zijn de nieuwe antistoffen nog niet getest.

Levenslang
Normale antistoffen tegen griepvirussen kunnen maar één versie van de ziekteverwekker aan. Je lichaam maakt deze complexe moleculen na een griepinfectie, en voor de rest van je leven blijven ze in je bloed aanwezig, altijd alert op de griepvirussen van toen.
Ze passen op de oppervlaktemoleculen van hun ‘eigen’ virus als een sleutel in een slot. Zelfs na negentig jaar kunnen ze hun beschermende werk nog doen. Maar tegen een nieuw virus kunnen ze niks beginnen.
De verschillen tussen griepvirussen zitten vooral aan de buitenkant, in de eiwitten hemagglutinine (H) en neuraminidase (N). Verschillende vormen daarvan hebben allemaal een nummer gekregen. En daarom heet de veroorzaker van de Spaanse griep H1N1, en het recente vogelgriepvirus H5N1. De vogelgriep die Nederland in 2003 teisterde en één man het leven kostte, was van het type H7N7.

Afgetroefd
Onderzoekers van het Nederlandse bedrijf Crucell hebben samen met collega’s van het Californische Scripps Institute veel tijd en moeite gestoken in het selecteren van antistoffen die het H-eiwit van meerdere griepvirussen kunnen herkennen. Ze wisten er meerdere uit het bloed van een gezonde vrijwilliger te vissen. Met de beste gingen ze aan de slag. Die antistof bleek aan te grijpen op een onderdeel van het viruseiwit dat bij twaalf van de zestien typen griepverwekkers precies hetzelfde is, schrijven ze in Science.
Helaas voor de Nederlanders zijn ze afgetroefd door concurrenten die net iets eerder vergelijkbare resultaten naar buiten brachten, die nog indrukwekkender zijn ook. Onderzoekers uit een aantal Amerikaanse labs onthulden vijf dagen eerder dat ze wel negen verschillende antistoffen hebben gevonden die hetzelfde kunnen. De krachtigste hebben ze bovendien al op muizen hebben getest.
Die muizen werden bijna allemaal goed beschermd, of ze de antistoffen nu voor of vlak na de griepinfectie toegediend kregen. Controlemuizen gingen binnen twee weken dood, op één taai beestje na.
De antistoffen werken tegen meerdere virussen omdat ze een onderdeel van het H-eiwit herkennen dat maar in twee vormen voorkomt. Blijkbaar zijn dit de enige vormen die geschikt zijn voor het werk dat het eiwit moet doen: de fusie tot stand brengen tussen het membraan dat het virus omhult en het celmembraan van de menselijke cel waar het zijn ziekmakende inhoud in kwijt wil.

Onbereikbaar
Dat deel van het eiwit zit niet helemaal aan de buitenkant, maar dicht tegen het membraan van het virus aan. Onbereikbaar voor antistoffen, zou je denken, want die zouden zich eerst door de buitenste laag heen moeten wringen. De muizenproef bewijst dat ze dat toch kunnen.
Je kunt je afvragen waarom het menselijk lichaam zelf niet op het idee komt om dit type antistoffen te maken. De reden is waarschijnlijk simpel: antistoffen tegen de buitenste laag van het virus zijn veel eenvoudiger te maken, en ook nog eens effectiever. Tegen dat ene virus dan.
Vooruitkijken, dat kan het lichaam niet, dus de snelste methode om het virus te verslaan wint altijd. Mensen kunnen wél nadenken over de toekomst en proberen die naar hun hand te zetten. Bijvoorbeeld door de antistoffen tegen griep al paraat te hebben voordat het virus zich aandient. Dat kan door vaccinatie.

Inenten
Nu zijn er twee manieren waarop je iemand kunt inenten tegen griep. De ene is door kant-en-klare antistoffen in te spuiten. Dat zou in principe nu al kunnen met de nieuw gevonden antistoffen, mits ze op grote schaal gekweekt kunnen worden – en dat zal wel lukken. Een nadeel van deze methode is, dat de bescherming na een tijdje minder wordt. Bovendien is het denkbaar dat de vreemde antistoffen het lichaam zelf aanvallen.
De tweede methode is iets inspuiten dat het afweersysteem stimuleert om eigenhandig de gewenste antistoffen te gaan maken. Zoiets gebeurt nu al – dat is de jaarlijkse griepprik – maar daarbij worden alleen antistoffen opgewekt die passen bij specifieke virussen, waarvan verwacht wordt dat ze in het komende jaar zullen toeslaan.
Dat kan waarschijnlijk dus beter: door losse onderdelen van de twee versies van het H-eiwit in te spuiten, die zelf ongevaarlijk zijn, of een type eiwit dat daar sterk op lijkt. Als dat goed werkt, zou iemand in één klap beschermd zijn tegen alle griepvirussen die er bestaan. Zoiets zou miljoenen levens kunnen redden.
Zo ver is het nog niet. Het staat natuurlijk ook niet voor honderd procent vast dat het zo ver komt. Maar het zou goed kunnen. En het mooiste is misschien wel, dat ook andere virussen met een soortgelijke aanpak bestreden kunnen worden. Ook ebola en hiv hebben stukken eiwit die altijd hetzelfde zijn.
Elmar Veerman

Naschrift: De resultaten van de andere groep zijn helemaal niet indrukwekkender, vindt een woordvoerder van Crucell. Want zijn bedrijf rapporteerde al in december vorig jaar www.plosone.org/article/info%3Adoi%2F... over dit type antistoffen, en had de beste toen ook al met succes op muizen getest. investors.crucell.com/C/132631/PR/200... Dus wie heeft wie nou afgetroefd?

Jianhua Sui e.a.: Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses, Nature Structural & Molecular Biology, 22 februari 2009
Damian C. Ekiert e.a.: Antibody recognition of a highly conserved influenza virus epitope, Sciencexpress, 26 februari 2009
noorderlicht.vpro.nl/artikelen/41559557/

flosz 23 maart 2009 14:01

2

Cover Story - Drug delivery
Haas, M. SciBX 2(10); doi:10.1038/scibx.2009.388
Published online March 12 2009

Bulking up immunity with instant Abs
by Michael J. Haas, Senior Writer

When Pfizer Inc. bought CovX Pharmaceuticals Inc. in 2007, the driver of the deal was the biotech's CovX-Body technology, which used a single antibody as a scaffold on which to build multiple product candidates that could be given via infusion. Pfizer may earn bonus miles from its acquisition, as CovX's cofounder at The Scripps Research Institute has now devised a way to produce the antibody therapeutics entirely in vivo, potentially obviating the need for infusions.
The technology, which is already licensed to Pfizer, uses a vaccine to induce the antibody scaffold, then a chemical agent to modify and direct the antibody against a specific disease target, thereby providing what the Scripps team has termed "instant immunity."
The group has shown proof of principle in mouse models of cancer and thinks the technology for chemically programmed antibodies could work against infectious diseases.
Unlike most antibodies, which bind their targets noncovalently, the antibody scaffolds used by Pfizer and Scripps are capable of binding their targets covalently, so that antibody and target fuse into a single molecule. Such antibodies were first reported in 1995 by a team led by Carlos Barbas III, chair of molecular biology at Scripps. The group found that mice injected with a small molecule (1,3-diketone) always developed antibodies that could covalently bind that molecule.1
According to team member Richard Lerner, now president at Scripps as well as a professor of chemistry and immunochemistry, this led to the hypothesis that the antibodies could be programmed against disease targets by linking a target-specific molecule to the antibody-inducing diketone.
Lerner and Barbas formed CovX in 2002 to commercialize these antibodies.

Abs training
The first-generation therapeutics are produced ex vivo and must be delivered by infusion. The latest Scripps work, also led by Barbas, investigated whether therapeutic antibodies could be produced and programmed entirely in vivo.
First, the team ascertained whether the anti-diketone antibody scaffold could find and bind a programming agent in vivo. To do this, they inoculated healthy mice with a vaccine based on a 1,3-diketone. Sixty-five days later they injected the mice with a programming agent composed of a diketone linked to an inhibitor of two antiangiogenic integrins: integrin v 3 and integrin v 5.
Experiments on serum pooled from the treated mice confirmed that the antibodies and programming agent had indeed found one another in vivo and fused into programmed antibodies (see Figure 1, "Production of chemically programmed antibodies in vivo"). www.nature.com/scibx/journal/v2/n10/f...

The team repeated the treatment with the vaccine and programming agent in mouse models of colon cancer and melanoma and observed decreases in tumor growth of more than 75% compared with that seen in controls.
The findings were published in the Proceedings of the National Academy of Sciences.2
In the paper, the team also suggested that programmed antibodies could induce immunity against infectious diseases such as HIV, malaria and pandemic flu.
To do so, Lerner told SciBX that humans could be inoculated with the diketone at any time to induce the programmable antibodies. "You could then give a chemical programming agent as needed to activate this reservoir of antibodies" against an emerging disease or even a chemical threat such as nerve gas to confer immunity almost instantaneously, he said. Lerner added that chemical programming agents could be taken orally.
Barbas noted that the approach would have lower production and prescription costs than infused antibody therapies.

Abs vantage points
Other researchers agreed that the technology is ready to test in cancer and potentially autoimmune disease, but they said direct evidence for its effectiveness against infectious disease is lacking.

Fons Uytdehaag, senior director of R&D strategy development at vaccine company Crucell N.V., said the Scripps approach has a big advantage over immunization with recombinant or vectored vaccines because it induces a universal immune response and memory, then rapidly directs that response against a disease target with the chemical programming agent.
Eric Guenzi, associate director of immunology research at cancer and autoimmune disease company MediGene AG, agreed that the instant immunity conferred by programmed antibodies offers a major selling point over conventional vaccines or infused antibody therapy.
"You could use this approach to re-create and reprogram therapeutic agents—which previously would have to be injected—by inducing instant immunity through vaccination with reactive compounds," he said. "With this system, your body does the job."
Guenzi said the results in cancer were promising, but he wanted to see animal studies showing that programmed antibodies could induce regression in established tumors and prevent metastasis. "It would be highly relevant to check the efficacy of the reprogrammed antibodies after the tumor has been established" for 2–3 weeks instead of beginning treatment before increasing tumor volume or tumor growth were measurable, as the Barbas collaborators did in their study, he said.
Guenzi also wanted to see experiments against more established cancer targets. "To my knowledge, the efficacy of inhibitors of v 3 and v 5 integrins has not been established in the clinic," he said.
Nevertheless, Guenzi noted that past approaches to treating cancer with therapeutic antibodies required adjuvant therapy. "Here they showed inhibition of tumor growth without recourse to adjuvant therapy, which is a clear advantage," he said.
Guenzi said the Barbas team's approach also allowed control over the immune response to self-antigens, which would avoid long-term safety issues that could arise when vaccinating against self-antigens.
"This is the first time I've read about something that combines an immunization approach with a short, intense reaction that controls the immune response and the memory of immune response," he said. "If you stop taking the programming agent, you stop the reactions, making the immune response controllable and reversible. This is a very important point for both cancer and autoimmune conditions."
Robert Rickert, associate professor of inflammatory diseases at the Burnham Institute for Medical Research, agreed that the technology provides a broad platform that could apply to multiple diseases. "The key will be to find appropriate therapeutic molecules or peptides that can be combined with the diketone" to make programming agents that are as effective as those used in the PNAS study, he said.
Barbas said his group has not encountered any significant difficulties in synthesizing programming agents. "Usually there is a site on a therapeutic peptide or small molecule that can be used for linkage" to the diketone, he said.

flosz 23 maart 2009 14:02

2

Ab extensions
There was less consensus about whether the technology could extend to infectious diseases.
Rickert said the technology's effectiveness against infection needs to be demonstrated, "but it is a perfectly valid extrapolation to make from these findings. The challenge with targeting pathogens will be that they are constantly evolving and mutating."
Thus, he said a programming agent should direct antibodies against a conserved site on a pathogen. Otherwise, the agent would be useless once the pathogen mutates—for example, as seasonal flu does.
MediGene's Guenzi was more cautious. "There is no evidence in the paper that this system could be used for non–self-antigens," he said.
Crucell's Uytdehaag agreed that preventing infection with programmed antibodies was a long way off. "For vaccination against viral diseases, it remains to be demonstrated whether programmed antibodies can neutralize—not just bind—a virus," he said.
Uytdehaag said that success in treating malaria, HIV and flu would depend on developing chemical programming agents with high affinity for the pathogens. He agreed with Rickert that such agents should target highly conserved epitopes to prevent escape mutations.
Uytdehaag also said there would be logistical issues in using the programmable antibodies for many infectious diseases.
"The broad and universal applicability of the technology to create instant immunity in the event of, for example, a flu pandemic, would require a pre-existing immunity to the [diketone] in the general population," he said. "Mass immunization early in life to generate a long-lived memory B cell response to the diketone is theoretically possible, but there may be ethical and regulatory issues involved with such an approach."
Rickert disagreed, noting that the diketone used by the Barbas team was inert, did not accumulate in the body and had no known human toxicity.
Lerner concurred with Rickert, adding that the compounds used by CovX and Pfizer to induce the antibody scaffolds have long-standing safety records in humans. Thus, he didn't anticipate significant ethical or regulatory hurdles to generating pre-existing, programmable immunity in the general population.
Barbas said his group has developed a variety of different antibodies that are also suitable for chemical programming and just as versatile as the anti-diketone antibodies. He added that his group is working to advance the technology described in PNAS to treat HIV, influenza and cancer.
Lerner said Scripps holds all of the IP related to chemically programmed antibodies and Pfizer has licensed the rights.
www.nature.com/scibx/journal/v2/n10/f...

flosz 26 maart 2009 04:39

2

Cover Story - Infectious disease
Haas, M. SciBX 2(9); doi:10.1038/scibx.2009.344
Published online March 5 2009
Anti-flubodies
by Michael J. Haas, Senior Writer

Two separate teams have isolated human antibodies that neutralize many variants of influenza antigen hemagglutinin A and prevent viral entry and infection. Both teams are developing their antibodies as therapeutics but are going after different markets: one is targeting pandemic flu outbreaks whereas the other wants to use its antibodies to treat or prevent seasonal flu in immunocompromised populations.
Though potentially useful additions to the anti-influenza armamentarium, the antibodies are not likely to replace vaccines as the primary defense against the disease.
Influenza antigen hemagglutinin A is a protein expressed on the viral surface that has two main regions: a globular head that enables viral attachment and fusion and a stem region that is buried in the viral envelope and undergoes a conformational change to allow viral entry and infection after fusion. There are 16 different hemagglutinin subtypes that fall into two groups. The 10 subtypes in Group 1 include H1, which occurs most frequently in seasonal influenza strains but also includes the pandemic 1918 flu virus, and H5, which includes the highly pathogenic strains of avian flu. Among the six Group 2 subtypes is H3, which also occurs in seasonal flu strains.
Another surface protein, neuraminidase, helps mature virus exit the infected host cell so that it can infect a new cell. Neuraminidase has nine subtypes, each of which can occur in combination with any hemagglutinin subtype. Thus, influenza viruses are designated according to their specific hemagglutinin and neuraminidase subtype—for example, H5N1.
Influenza infections and vaccinations mostly stimulate antibodies against the hemagglutinin head because it is exposed to the immune system during viral fusion and entry. The problem is that the head region mutates readily without losing its attachment or fusion function, thereby evading anti-hemagglutinin antibodies.
Such mutations also make it difficult to predict which influenza strain will be in circulation from one season to the next. Thus, there is a market for therapeutics or prophylactics that are simultaneously effective against many strains of seasonal and/or pandemic strains.
A team from the Dana-Farber Cancer Institute, the Burnham Institute for Medical Research and the Centers for Disease Control and Prevention (CDC) set out to isolate antibodies that would block multiple strains of H5N1 influenza.
They screened a human antibody library against recombinant H5 and isolated three leads that neutralized all nine Group 1 subtypes that they tested against in human cell lines.
Mice injected with any of three antibodies one hour before challenge with H5N1 or up to 48 hours after viral challenge survived and showed few or no clinical signs of infection. The antibodies also protected mice from two lethal strains of H1N1.
X-ray crystallography of an H5 hemagglutinin-antibody cocrystal showed that the antibody bound an epitope on the hemagglutinin stem that is conserved across all Group 1 subtypes.
All six Group 2 subtypes had a different conserved epitope at this stem position.
In a report in Nature Structural and Molecular Biology, the team said their results suggest that the antibodies could provide broad-spectrum protection against pandemic and seasonal flu viruses.1
On a conference call, team coleader Wayne Marasco, associate professor of medicine at Dana-Farber and Harvard Medical School, said the group is developing the antibodies primarily to contain pandemic outbreaks. The antibodies would be given to family members, co-workers and healthcare workers who come in close contact with an infected individual, he said.
"These antibodies are ready to go," team coleader Robert Liddington told SciBX. They could "snuff out a pandemic."
Liddington is professor and director of the infectious disease program at Burnham. Ruben Donis, chief of the CDC's molecular virology and vaccines branch, also co-led the Nature Structural and Molecular Biology study.

Another flu in the ointment
In addition to the Nature Structural and Molecular Biology paper, two papers from Crucell N.V. and others described the identification of human antibodies that could neutralize different hemagglutinin subtypes and detailed the underlying mechanism of how the neutralization occurred.2, 3
In a paper published in PLoS One, the team constructed combinatorial display libraries using antibodies recovered from the serum of individuals inoculated against H1N1 virus and then screened those libraries against recombinant H5 hemagglutinin. The lead antibody from that screen, CR6261, neutralized all six Group 1 subtypes of hemagglutinin it was tested against; the team did not test the other four subtypes.
The antibody also protected mice from challenge with lethal strains of H5N1 or H1N1.
In a follow-on study in Science, another Crucell-led team reported structural studies of an H5 hemagglutinin–CR6261 cocrystal that showed that the antibody targeted the same conserved epitope identified in the Nature Structural and Molecular Biology study.
The PLoS One team, led by Crucell CSO Jaap Goudsmit, also included researchers from The University of Hong Kong's Queen Mary Hospital, Algonomics N.V., Wageningen University, Johann Wolfgang Goethe University and Bambino Gesú Children's Hospital.
The Science team was led by Ian Wilson, professor of molecular biology at The Scripps Research Institute, and included Goudsmit and other researchers from both Crucell and Scripps.
Scripps' Wilson told SciBX that a team of researchers from Scripps and Sea Lane Biotechnologies LLC had previously reported antibodies that neutralized both the H1 and H5 subtypes.4 However, the researchers could not identify the actual hemagglutinin epitope targeted by the antibodies because they did not have a hemagglutinin-antibody cocrystal structure.

flosz 26 maart 2009 04:40

2

New flu tools
Although the antibodies identified by the Nature Structural and Molecular Biology and Crucell teams could help treat or prevent both seasonal and pandemic influenza, logistical and commercial drawbacks might limit utility.
Penny Heaton, CMO of Novavax Inc., noted that more than one dose probably would be required during the course of a season or pandemic because the typical antibody has a half-life of four to six weeks.
Thus, she said, "antibodies are not the be-all or end-all treatment for pandemic or seasonal flu."
Novavax has virus-like particle (VLP)-based vaccines against pandemic influenza in Phase II testing and expects to begin two Phase IIa trials of a VLP-based vaccine against seasonal flu this year.
Bill Enright, president and CEO of Vaxin Inc., agreed that half-life is important.
Vaxin is developing seasonal and pandemic influenza vaccines that express H1 or H5 in an adenovirus vector. The pandemic vaccine is in Phase I testing; the company hopes to begin Phase II testing of the seasonal vaccine this year. The vaccines are delivered by intranasal inhalation rather than intramuscular injection.
"We have seen immune responses to our vaccines that last more than one year," Enright said.
Alan Shaw, president and CEO of VaxInnate Corp., also thinks an influenza antibody would face several hurdles. He said the doses needed to protect mice in both the Nature Structural and Molecular Biology and Crucell studies translated to huge doses in humans: about 1,500 mg for a 100-kg person. Thus, Shaw thinks it would be very hard to produce and distribute sufficient quantities of the antibodies and that production and prescription costs would be prohibitive.
VaxInnate has H1- and H5-based vaccines in Phase I testing for seasonal and pandemic influenza.
Both Larry Smith, VP of vaccine research at Vical Inc., and George Kemble, VP of R&D and general manager of vaccines at the MedImmune Inc. subsidiary of AstraZeneca plc, agreed that the antibodies faced major logistical hurdles.
Smith pointed to the unknown treatment dose, unknown duration of protection and potentially high cost of antibody protection as significant disadvantages.
Last year Vical completed Phase I testing of a plasmid DNA vaccine encoding H5 to prevent pandemic influenza.
"The quantity of material required to protect an adult population from infection for three to six months or more during a pandemic is staggering," Kemble said.
He suggested that using the antibodies to treat individual cases of influenza would be a more manageable option. "Having another tool at the bedside to intervene in what could be a severe or lethal infection would complement, but not replace," prophylactic vaccinations, he said.
MedImmune markets FluMist, a live attenuated influenza vaccine (LAIV) to prevent seasonal flu. The company also has an LAIV in Phase I testing to prevent pandemic flu.
Goudsmit noted that Crucell's CR6261 also protected ferrets from influenza up to six days after infection at doses that are feasible in humans. The company plans to develop CR6261 to treat or prevent seasonal influenza in at-risk populations. These include children, the elderly and immunocompromised individuals who are not always well protected by marketed vaccines.
According to Goudsmit, seasonal flu infects about 200,000 elderly people in the U.S.—of which about 35,000 die—and the U.S. represents about half of the $2.2 billion global market of elderly patients. "The size of the problem observed in these populations with seasonal flu vaccines indicates a major unmet medical need," he said.
On the pandemic front, Heaton said antibodies might not be the best approach.
"Pandemic infection is so aggressive that the early-stage immune response causes respiratory problems" and eventually pneumonia, she noted. The reason is the virus spreads through the respiratory system quickly—a process that is inhibited primarily by the immune response to neuraminidase. Thus, an anti-hemagglutinin antibody might not halt respiratory spread of a pandemic virus.
Heaton said Novavax's pandemic and seasonal influenza vaccines offer broader protection than antibodies because they are based on recombinant hemagglutinin, neuraminidase and one other viral surface protein, matrix protein 1. She said this combination induces three distinct immune responses in a vaccinated individual: antibodies against hemagglutinin, a cell-mediated response to neuraminidase that slows the progression to pneumonia and the induction of cytotoxic lymphocytes that kill infected cells.
Heaton added that it was almost impossible to completely prevent viral entry. Thus, "depending on an anti-hemagglutinin antibody alone is a very tall order," she said.
Vical's Smith agreed. Although developing a vaccine from the findings of the Nature Structural and Molecular Biology and Crucell teams would require more work than developing the antibodies, "vaccination ultimately would be a better strategy for controlling the morbidity and mortality of influenza viruses," he said.

Antibody flight plans
Marasco said the Nature Structural and Molecular Biology team will seek partners in government or industry to develop the antibodies. The team hopes to take the antibodies into the clinic by the winter of 2011–2012.
Liddington said the team's other priorities include isolating antibodies against the Group 2 epitope and performing additional screens to identify back-up antibodies against Group 1 subtypes. A combination of antibodies targeting Group 1 and Group 2 subtypes could be used against any flu virus, he said.
Indeed, Goudsmit said Crucell has already isolated an antibody that targets the conserved Group 2 epitope and plans to develop it in combination with CR6261 to treat or prevent seasonal flu in at-risk populations.
The company expects to start clinical trials within the next two years, he said.
The findings reported in Nature Structural and Molecular Biology are patented by Dana-Farber and Burnham and are available for licensing, according to Ruth Emyanitoff, senior licensing manager at Dana-Farber. The findings reported in PLoS One and Science are patented by Crucell.
www.nature.com/scibx/journal/v2/n9/pd...

eddy59 26 maart 2009 07:32

0

Crucell teams could help treat or prevent both seasonal and pandemic influenza, logistical and commercial drawbacks might limit utility.
Voor logostiek en commerce zijn oplossingen te bedenken.
Ik denk dat we 500 mega productie faciliteiten nodig hebben om aan de vraag te voldoen bij een pandemie.
Regeringen wereldwijd kunnen Crucell inhuren om dit voor ze te regelen.( uiteraard moeten ze vooruit betalen)
Eddy

flosz 18 mei 2009 19:34

2

quote:
flosz schreef:
Published Online February 26, 2009
Science DOI: 10.1126/science.1171491
REPORTS
Submitted on January 27, 2009
Accepted on February 19, 2009

Antibody Recognition of a Highly Conserved Influenza Virus Epitope
Damian C. Ekiert 1, Gira Bhabha 1, Marc-André Elsliger 1, Robert H. E. Friesen 2, Mandy Jongeneelen 2, Mark Throsby 2, Jaap Goudsmit 2, Ian A. Wilson 3*
1 Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
2 Crucell Holland BV, Archimedesweg 4-6, 2301 CA Leiden, The Netherlands.
3 Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
* To whom correspondence should be addressed.
Ian A. Wilson , E-mail: wilson@scripps.edu
Influenza virus presents a significant and persistent threat to public health worldwide, and current vaccines provide immunity to viral isolates similar to the vaccine strain. High-affinity antibodies against a conserved epitope could provide immunity to the diverse influenza subtypes and protection against future pandemic viruses. Co-crystal structures were determined at 2.2 and 2.7 Å resolutions for broadly neutralizing human antibody CR6261 Fab in complexes with the major surface antigen (hemagglutinin, HA) from viruses responsible for the 1918 H1N1 influenza pandemic and a recent lethal case of H5N1 avian influenza. In contrast to other structurally characterized influenza antibodies, CR6261 recognizes a highly conserved helical region in the membrane-proximal stem of HA1/HA2. The antibody neutralizes the virus by blocking conformational rearrangements associated with membrane fusion. The CR6261 epitope identified here should accelerate the design and implementation of improved vaccines that can elicit CR6261-like antibodies, as well as antibody-based therapies for the treatment of influenza.
www.sciencemag.org/cgi/content/abstra...

Perspective abstract
________________________________________
Nature Immunology 10, 573 - 578 (2009)
Published online: 18 May 2009 | doi:10.1038/ni.1746
HIV-1 and influenza antibodies: seeing antigens in new ways
Peter D Kwong1 & Ian A Wilson2
________________________________________
Abstract
New modes of humoral recognition have been identified by studies of antibodies that neutralize human immunodeficiency virus type 1 and influenza A viruses. Understanding how such modes of antibody-antigen recognition can occur in the context of sophisticated mechanisms of humoral evasion has implications for the development of effective vaccines. Here we describe eight modes of antibody recognition first observed with human immunodeficiency virus type 1. Similarities to four of these modes have been identified with antibodies to a conserved 'stem' epitope on influenza A viruses. We outline how each of these different modes of antibody recognition is particularly suited to overcoming a specific viral evasion tactic and assess potential routes of re-elicitation in vaccine settings.
Top of page
________________________________________
1. Peter D. Kwong is with the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
e-mail: pdkwong@nih.gov
2. Ian A. Wilson is in the Department of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
www.nature.com/ni/journal/v10/n6/abs/...

flosz 16 juni 2009 01:48

3

www.sciencemag.org/cgi/data/1171491/D...

ved 17 februari 2010 12:36

1

Dana-Farber And Sanford-Burnham Institute License Flu-Targeting Antibodies

Article Date: 09 Feb 2010 - 0:00 PST

Dana-Farber Cancer Institute and the Sanford-Burnham Medical Research Institute have signed a license agreement with Genentech, a wholly owned member of the Roche group, and Roche, that grants the companies exclusive rights to manufacture, develop and market human monoclonal antibodies to treat and protect against group 1 influenza viruses. These viruses include the strains for the current seasonal and H1N1 influenzas. Genentech and Roche also have a non-exclusive right to manufacture, develop and market diagnostic tests for group 1 influenza.

The discovery of the antibodies was first reported by Wayne A. Marasco, MD, PhD, associate professor of medicine at Dana-Farber and Harvard Medical School; Robert Liddington, PhD, professor and director, Infectious and Inflammatory Disease Center at Sanford-Burnham; and Ruben Donis, PhD, chief of the Molecular Virology and Vaccines Branch at the Centers for Disease Control and Prevention, in Nature Structural and Molecular Biology in February 2009.

They demonstrated that the newly identified antibodies attach to the stem region of the viral proteins (hemagglutinin), rather than to the head region, the standard target of current influenza vaccines. Binding to the highly conserved stem region prevents changes in the protein that are necessary for viral entry into the host cell, thereby inhibiting further infection of host cells and the rise of escape mutants. Standard influenza vaccines that consist of an attenuated, or killed, virus typically stimulate antibodies against the protein's head. These vaccines are less effective as the head region is prone to change, leading to the rise of forms of the virus that can evade neutralizing antibodies.

Complete terms of the agreement are not public, but Dana-Farber and Sanford-Burnham will receive license fees and may receive milestone payments and royalties.

Source
Dana-Farber Cancer Institute
Sanford-Burnham Medical Research Institute

www.medicalnewstoday.com/articles/178...

aossa 18 februari 2010 14:44

3

Al gelezen? (met dank aan perseazes, gepost op IV)

New Class of Monoclonal Antibodies against Severe
Influenza: Prophylactic and Therapeutic Efficacy in
Ferrets

Robert H. E. Friesen1*, Wouter Koudstaal1, Martin H. Koldijk1, Gerrit Jan Weverling1, Just P. J.
Brakenhoff1, Peter J. Lenting1, Koert J. Stittelaar2, Albert D. M. E. Osterhaus2,3, Ronald Kompier1, Jaap
Goudsmit1
1 Crucell Holland BV, Leiden, The Netherlands, 2 ViroClinics BV, Rotterdam, The Netherlands, 3 Department of Virology, ErasmusMC, Rotterdam, The Netherlands

Background: The urgent medical need for innovative approaches to control influenza is emphasized by the widespread resistance of circulating subtype H1N1 viruses to the leading antiviral drug oseltamivir, the pandemic threat posed by the occurrences of human infections with highly pathogenic avian H5N1 viruses, and indeed the evolving swine-origin H1N1 influenza pandemic. A recently discovered class of human monoclonal antibodies with the ability to neutralize a broad spectrum of influenza viruses (including H1, H2, H5, H6 and H9 subtypes) has the potential to prevent and treat influenza in
humans. Here we report the latest efficacy data for a representative antibody of this novel class.

Methodology/Principal Findings: We evaluated the prophylactic and therapeutic efficacy of the human monoclonal antibody CR6261 against lethal challenge with the highly pathogenic avian H5N1 virus in ferrets, the optimal model of
human influenza infection. Survival rates, clinically relevant disease signs such as changes in body weight and temperature, virus replication in lungs and upper respiratory tract, as well as macro- and microscopic pathology were investigated.
Prophylactic administration of 30 and 10 mg/kg CR6261 prior to viral challenge completely prevented mortality, weight loss and reduced the amount of infectious virus in the lungs by more than 99.9%, abolished shedding of virus in pharyngeal secretions and largely prevented H5N1-induced lung pathology. When administered therapeutically 1 day after challenge, 30 mg/kg CR6261 prevented death in all animals and blunted disease, as evidenced by decreased weight loss and temperature rise, reduced lung viral loads and shedding, and less lung damage.

Conclusions/Significance: These data demonstrate the prophylactic and therapeutic efficacy of this new class of human monoclonal antibodies in a highly stringent and clinically relevant animal model of influenza and justify clinical development of this approach as intervention for both seasonal and pandemic influenza.
Citation: Friesen RHE, Koudstaal W, Koldijk MH, Weverling GJ, Brakenhoff JPJ, et al. (2010) New Class of Monoclonal Antibodies against Severe Influenza:
Prophylactic and Therapeutic Efficacy in Ferrets. PLoS ONE 5(2): e9106. doi:10.1371/journal.pone.0009106
Editor: Linqi Zhang, Tsinghua University, China

Received June 24, 2009; Accepted January 21, 2010; Published February 8, 2010
Copyright: _ 2010 Friesen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was funded by Crucell Holland BV (http://www.crucell.com). The funder had a role in study design, data analysis, decision to publish and
preparation of the manuscript, but not in execution of the experiments and collection of the data.
Competing Interests: The authors state that they have a financial interest. RF, WK, MK, GJW, JB, PL, RK, and JG are employees of Crucell Holland BV. KS and AO are employees of ViroClinics BV. AO is furthermore an employee of the ErasmusMC, Rotterdam.

www.plosone.org/article/fetchObjectAt...

maxen 18 februari 2010 15:21

2

quote:
aossa schreef:
New Class of Monoclonal Antibodies against Severe
Influenza: Prophylactic and Therapeutic Efficacy in
Ferrets

De flumAbs werkten al voor muizen, het blijkt nu ook te werken voor ferrets, die dichter bij mensen staan.

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