 |
|
Scientists identify lab-made proteins that neutralize multiple strains of seasonal and pandemic flu
February 23, 2009Scientists have identified a small family of lab-made proteins that neutralize a broad range of influenza A viruses, including the H5N1 avian virus, the 1918 pandemic influenza virus and seasonal H1N1 flu viruses. These human monoclonal antibodies, identical infection-fighting proteins derived from the same cell lineage, also were found to protect mice from illness caused by H5N1 and other influenza A viruses. Because large quantities of monoclonal antibodies can be made relatively quickly, after more testing, these influenza-specific monoclonal antibodies potentially could be used in combination with antiviral drugs to prevent or treat the flu during an influenza outbreak or pandemic.
A report describing the research, supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health as well as the Centers for Disease Control and Prevention, appears online today in Nature Structural & Molecular Biology. Wayne Marasco, M.D., Ph.D., associate professor of medicine at the Dana-Farber Cancer Institute and Harvard Medical School in Boston led the research team, which included collaborators from the Burnham Institute for Medical Research in La Jolla, Calif., and the CDC in Atlanta.
"This is an elegant research finding that holds considerable promise for further development into a medical tool to treat and prevent seasonal as well as pandemic influenza," notes NIAID Director Anthony S. Fauci, M.D. "In the event of an influenza pandemic, human monoclonal antibodies could be an important adjunct to antiviral drugs to contain the outbreak until a vaccine becomes available."
Using standard methods of production, initial doses of a new influenza vaccine to fight pandemic influenza would be expected to take four to six months to produce.
Key to their research, Dr. Marasco and his colleagues discovered and described the atomic structure of an obscure but genetically stable region of the influenza virus to which their monoclonal antibodies bind. The hidden part of the influenza virus is in the neck below the peanut-shaped head of the hemagglutinin (HA) protein. HA and neuraminidase are the two main surface proteins on the influenza virus.
The scientists also identified a new mechanism of antibody action against influenza: Once the antibody binds, the virus cannot change its shape, a step required before it can fuse with and enter the cell it is attempting to infect.
Dr. Marasco, Jianhua Sui, M.D., Ph.D., and other Dana-Farber colleagues began their study with avian flu viruses. They scanned tens of billions of monoclonal antibodies produced in bacterial viruses, or bacteriophages, and found 10 antibodies active against the four major strains of H5N1 avian influenza viruses. Encouraged by these findings, they collaborated with Ruben O. Donis, Ph.D., of the CDC Influenza Division, and found that three of these monoclonal antibodies had broader neutralization capabilities when tested in cell cultures and in mice against representative strains of other known influenza A viruses.
Influenza A viruses can include any one of the 16 known subtypes of HA proteins, which fall into two groups, Group 1 and Group 2. Their monoclonal antibodies neutralized all testable viruses containing the 10 Group 1 HAs--which include the seasonal H1 viruses, the H1 virus that caused the 1918 pandemic and the highly pathogenic avian H5 subtypes--but none of the viruses containing the six Group 2 HAs.
Simultaneously, Dr. Marasco's group teamed up with Robert C. Liddington, Ph.D., professor and chair of the Infectious and Inflammatory Disease Center at Burnham, to determine the atomic structure of one of their monoclonal antibodies bound to the H5N1 HA. Their detailed picture shows one arm of the antibody inserted into a genetically stable pocket in the neck of the HA protein, an interaction that blocks the shape change required for membrane fusion and virus entry into the cell.
When they surveyed more than 6,000 available HA genetic sequences of the 16 HA subtypes, they found the pockets to be very similar within each Group but to be significantly different between the two Groups. The genetically stable pockets, they note, may be a result of evolutionary constraints that enable virus-cell fusion. This could also explain why they did not detect so-called escape mutants, viruses that elude the monoclonal antibodies through genetic mutation.
"One of the most remarkable findings of our work is that we identified a highly conserved region in the neck of the influenza hemagglutinin protein to which humans rarely make antibodies," says Dr. Marasco. "We believe this is because the head of the hemagglutinin protein acts as a decoy by constantly undergoing mutation and thereby attracting the immune system to produce antibodies against it rather than against the pocket in the neck of the protein."
Their findings could also assist vaccine developers. Current influenza vaccines target the constantly mutating head of the HA protein and do not readily generate antibodies against the conserved region in the neck.
"An important goal is to redirect the immune response of vaccines to this invariable region of the hemagglutinin to try to obtain durable lifelong immunity," Dr. Marasco states.
The monoclonal antibodies identified in their paper are very well-characterized, Dr. Marasco notes, and he is optimistic about their further clinical development. "These are fully human monoclonal antibodies that are ready for advanced preclinical testing," he says. He currently is arranging to use NIAID research resources to take the next steps: first, testing the antibodies in ferrets, the gold standard animal model for influenza, and then developing a clinical grade version of one antibody that could enter human clinical trials as soon as 18 months from when the development program begins. Should the antibodies prove safe and effective in humans, it could take several years to develop a licensed product.
Despite the availability of influenza drugs and vaccines, seasonal influenza still kills more than 250,000 people worldwide each year. During seasonal flu outbreaks, monoclonal antibodies could be used to treat individuals with impaired immunity due to pre-existing medical conditions or advanced age. In the event of an influenza pandemic, these individuals plus others at risk--for example, first responders and medical personnel and exposed family members and coworkers--could also benefit from this type of therapy.
NIH/National Institute of Allergy and Infectious Diseases
Using standard methods of production, initial doses of a new influenza vaccine to fight pandemic influenza would be expected to take four to six months to produce.
Key to their research, Dr. Marasco and his colleagues discovered and described the atomic structure of an obscure but genetically stable region of the influenza virus to which their monoclonal antibodies bind. The hidden part of the influenza virus is in the neck below the peanut-shaped head of the hemagglutinin (HA) protein. HA and neuraminidase are the two main surface proteins on the influenza virus.
The scientists also identified a new mechanism of antibody action against influenza: Once the antibody binds, the virus cannot change its shape, a step required before it can fuse with and enter the cell it is attempting to infect.
Dr. Marasco, Jianhua Sui, M.D., Ph.D., and other Dana-Farber colleagues began their study with avian flu viruses. They scanned tens of billions of monoclonal antibodies produced in bacterial viruses, or bacteriophages, and found 10 antibodies active against the four major strains of H5N1 avian influenza viruses. Encouraged by these findings, they collaborated with Ruben O. Donis, Ph.D., of the CDC Influenza Division, and found that three of these monoclonal antibodies had broader neutralization capabilities when tested in cell cultures and in mice against representative strains of other known influenza A viruses.
Influenza A viruses can include any one of the 16 known subtypes of HA proteins, which fall into two groups, Group 1 and Group 2. Their monoclonal antibodies neutralized all testable viruses containing the 10 Group 1 HAs--which include the seasonal H1 viruses, the H1 virus that caused the 1918 pandemic and the highly pathogenic avian H5 subtypes--but none of the viruses containing the six Group 2 HAs.
Simultaneously, Dr. Marasco's group teamed up with Robert C. Liddington, Ph.D., professor and chair of the Infectious and Inflammatory Disease Center at Burnham, to determine the atomic structure of one of their monoclonal antibodies bound to the H5N1 HA. Their detailed picture shows one arm of the antibody inserted into a genetically stable pocket in the neck of the HA protein, an interaction that blocks the shape change required for membrane fusion and virus entry into the cell.
When they surveyed more than 6,000 available HA genetic sequences of the 16 HA subtypes, they found the pockets to be very similar within each Group but to be significantly different between the two Groups. The genetically stable pockets, they note, may be a result of evolutionary constraints that enable virus-cell fusion. This could also explain why they did not detect so-called escape mutants, viruses that elude the monoclonal antibodies through genetic mutation.
"One of the most remarkable findings of our work is that we identified a highly conserved region in the neck of the influenza hemagglutinin protein to which humans rarely make antibodies," says Dr. Marasco. "We believe this is because the head of the hemagglutinin protein acts as a decoy by constantly undergoing mutation and thereby attracting the immune system to produce antibodies against it rather than against the pocket in the neck of the protein."
Their findings could also assist vaccine developers. Current influenza vaccines target the constantly mutating head of the HA protein and do not readily generate antibodies against the conserved region in the neck.
"An important goal is to redirect the immune response of vaccines to this invariable region of the hemagglutinin to try to obtain durable lifelong immunity," Dr. Marasco states.
The monoclonal antibodies identified in their paper are very well-characterized, Dr. Marasco notes, and he is optimistic about their further clinical development. "These are fully human monoclonal antibodies that are ready for advanced preclinical testing," he says. He currently is arranging to use NIAID research resources to take the next steps: first, testing the antibodies in ferrets, the gold standard animal model for influenza, and then developing a clinical grade version of one antibody that could enter human clinical trials as soon as 18 months from when the development program begins. Should the antibodies prove safe and effective in humans, it could take several years to develop a licensed product.
Despite the availability of influenza drugs and vaccines, seasonal influenza still kills more than 250,000 people worldwide each year. During seasonal flu outbreaks, monoclonal antibodies could be used to treat individuals with impaired immunity due to pre-existing medical conditions or advanced age. In the event of an influenza pandemic, these individuals plus others at risk--for example, first responders and medical personnel and exposed family members and coworkers--could also benefit from this type of therapy.
NIH/National Institute of Allergy and Infectious Diseases
Monoclonal Antibodies Current Events and Monoclonal Antibodies News RSSNew cancer target for non-Hodgkin's lymphoma
Physician-scientists from Weill Cornell Medical College have discovered a molecular mechanism that may prove to be a powerful target for the treatment of non-Hodgkin's lymphoma, a type of cancer that affects lymphocytes, or white blood cells.
Largest gene study of childhood IBD identifies 5 new genes
In the largest, most comprehensive genetic analysis of childhood-onset inflammatory bowel disease (IBD), an international research team has identified five new gene regions, including one involved in a biological pathway that helps drive the painful inflammation of the digestive tract that characterizes the disease.
Study reveals a 'missing link' in immune response to disease
The immune system's T cells have the unique responsibilities of being both jury and executioner. They examine other cells for signs of disease, including cancers or infections, and, if such evidence is found, rid them from the body. Precisely how T cells shift so swiftly from one role to another, however, has been a mystery.
Breakthrough in fight against Hendra virus
There has been a breakthrough in the fight against the deadly Hendra virus following the development of a treatment which shows great potential to save the lives of people who become infected with the virus.
Immunotherapy demonstrates long-term success in treating lymphoma
Targeted immunotherapy has been an attractive new therapeutic area for a number of cancers because it has the potential to destroy tumor cells without damaging surrounding normal tissue. New study results demonstrate high success rates using specialized white blood cells to prevent or treat lymphoma associated with the Epstein-Barr virus (EBV-lymphoma) in patients who have received a hematopoietic stem cell transplant (HSCT).
Adding cetuximab to chemotherapy reduces advanced lung cancer death risk by 13 percent
Patients with advanced non-small cell lung cancer who are given cetuximab (Erbitux) in addition to chemotherapy are 13% less likely to die than those who receive chemotherapy alone, regardless of which chemotherapy drug cocktail is used, new research finds. They also experience slower disease progression and an increased chance of tumour shrinkage.
New chemically-activated antigen could expedite development of HIV vaccine
Scientists working to develop a vaccine for the human immunodeficiency virus (HIV) report they have created the first antigen that induces protective antibodies capable of blocking infection of human cells by genetically-diverse strains of HIV.
Researchers induce HIV-neutralizing antibodies that recognize HIV-1 envelope protein, lipids
For the first time, researchers have experimentally induced antibodies that neutralize HIV-1 and simultaneously recognize both HIV-1 envelope protein and lipids.
Budesonide is not beneficial for the treatment of diarrhea in metastatic melanoma patients
Patients with stage III or IV melanoma taking ipilimumab and the oral steroid budesonide to reduce side effects did not have less diarrhea, a known side effect of ipilimumab.
First human gets new antibody aimed at hepatitis C virus
Building upon a series of successful preclinical studies, researchers at MassBiologics of the University of Massachusetts Medical School (UMMS) today announced the beginning of a Phase 1 clinical trial, testing the safety and activity of a human monoclonal antibody they developed that can neutralize the Hepatitis C virus (HCV).
More Monoclonal Antibodies Current Events and Monoclonal Antibodies News Articles
 |
Therapeutic Monoclonal Antibodies: From Bench to Clinic by Zhiqiang An (Editor) 70-chapter authoritative reference that covers therapeutic monoclonal antibody discovery, development, and clinical applications while incorporating principles, experimental data, and methodologies. First book to address the discovery and development of antibody therapeutics in their entirety. Most chapters contain experimental data to illustrate the principles described in them. Authors provide detailed methodologies that readers can take away with them and use in their own laboratories |
 |
Monoclonal Antibodies in Biotechnology: Theoretical and Practical Aspects (Cambridge Studies in Biotechnology) by Kenneth C. McCullough (Author), Raymond E. Spier (Author) This volume provides a complete description of the principles, methodologies and applications of monoclonal antibodies, one of the most exciting developments to occur in biotechnology in recent years, and a powerful technology for modern industry and science. The immune system and the role of the antibody are described and full details are given on how the hybridomas are formed, isolated, and maintained in culture such that the required antibody can be produced to a high degree of purity. The authors describe all the methodologies involved, all the reagents and solutions and all the assay conditions required for their production. The material is presented to enable research and development managers to make choices as to which are the most suitable techniques for their requirements. The... |
 |
Monoclonal Antibodies: Methods and Protocols (Methods in Molecular Biology) by Maher Albitar (Editor) Monoclonal Antibodies: Methods and Protocols examines a collection of state-of-the-art methods that employ monoclonal antibodies in a clinical setting with opening chapters focusing on the gold standard method for generating mouse monoclonal antibodies through hybridoma technology, future methods for engineering recombinant and humanized antibodies, methods for engineering soluble Fc fusion protein, and the use of antibodies and flow cytometry in the quantification of cell signaling proteins. Specific chapters describe how antibodies are used for the diagnosis and classification of hematologic diseases. Subsequent chapters examine the advantages and most recent advances of using bead-based immunoassays, including the ability of bead-based technology to multiplex and analyze several... |
 |
Therapeutic Antibodies: Methods and Protocols (Methods in Molecular Biology) by Antony S. Dimitrov (Editor) With revenues from the top five therapeutic antibodies accounting for a majority of the recent pharmaceutical sales, the research and development in the field has exploded over the past several years and is expected to grow with new emerging monoclonal antibodies like Numax, Lucentis, Actemra, and others. In Therapeutic Antibodies: Methods and Protocols, leading experts from academic laboratories and biotechnology companies present an extensive set of protocols for the discovery and development of therapeutic antibodies, featuring sections devoted to recombinant antigens, antibody libraries, antibody discovery, antibody engineering, and antibody preclinical development. Written in the highly successful Methods in Molecular Biology™ series format, the chapters contain brief... |
 |
Monoclonal Antibodies, Third Edition: Principles and Practice by James W. Goding (Author) Monoclonal Antibodies now have applications in virtually all areas of biology and medicine, and much of the world's biotechnology industry has its foundations in the exploitation of this technology. The Third Edition of this well established book meets the needs of both newcomers to the area and experienced researchers, by providing an integrated treatment of both the production and application of monoclonal antibodies. As in previous editions, detailed and critical accounts of the theory, production, purification, fragmentation, storage and radiolabelling of monoclonal antibodies are given, along with descriptions of their use in antigen characterization, affinity chromatography and immunofluorescence. The present volume has been comprehensively updated to cover recent rapid advances,... |
|
Hybridomas and Monoclonal Antibodies [VHS] Starring: Charles Brinton, Sarah Wood | |
 |
"Glycophorin A - Concentrated Monoclonal Antibodies, Diagnostic BioSystems - Model MOB 066" by DBS Glycophorin A - Concentrated Monoclonal Antibodies, Diagnostic BioSystems - Model MOB 066 : Antibodies are intended for research use only and should not be used for diagnostic or therapeutic work. Store all antibodies at 4 to 8 degrees C (39 to 46 degrees F) unless otherwise specified. For more information, go to our website or call your custome |
 |
Rat Monoclonal Antibody to ORF-73 of Human Herpesvirus 8 (HHV-8) (100 µg) by Advanced Biotech Rat monoclonal antibody to latent nuclear antigen (LNA-1) ORF-73 of human herpesvirus 8 (HHV-8). This antibody originates from ascitic fluid and is purified by protein G agarose chromatography. |
 |
Monoclonal Antibodies (Basics (Bios Scientific Publishers).) by H. Zola (Author) A review of what needs to be done to realise the potential of monoclonal antibodies. The book assesses the competing technologies with advice on the best approach for a particular situation. |
 |
Current Trends in Monoclonal Antibody Development and Manufacturing (Biotechnology: Pharmaceutical Aspects) by Steven J. Shire (Editor), Wayne Gombotz (Editor), Karoline Bechtold-Peters (Editor), James Andya (Editor) Monoclonal antibodies represent one of the fastest growing areas of new drug development within the pharmaceutical industry. Several blockbuster products have been approved over the past several years including Rituxan, Remicade, Avastin, Humira, and Herceptin. In addition, over 300 new drugs are currently in clinical trials. With both large, established biotechnology companies and small start-ups involved in the development of this important class of molecules, monoclonal antibodies products will become increasingly prevalent over the next decade. Recently the regulatory review of monoclonal antibodies has been moved from Center for Biologics and Research to the Center for Drug Evaluation and Research (CDER) division of the US Food and Drug Administration. It is anticipated... |
| © 2009 BrightSurf.com |