Therapeutic antibodies: current state and future trends--is a paradigm change coming soon?

Antibody-based therapeutics currently enjoy unprecedented success, growth in research and revenues, and recognition of their potential. It appears that the promise of the "magic bullet" has largely been realized. There are currently 22 monoclonal antibodies (mAbs) approved by the United States Food and Drug Administration (FDA) for clinical use and hundreds are in clinical trials for treatment of various diseases including cancers, immune disorders, and infections. The revenues from the top five therapeutic antibodies (Rituxan, Remicade, Herceptin, Humira, and Avastin) nearly doubled from $6.4 billion in 2004 to$11.7 billion in 2006. During the last several years major pharmaceutical companies raced to acquire antibody companies, with a recent example of MedImmune being purchased for $15.6 billion by AstraZeneca. These therapeutic and business successes reflect the major advances in antibody engineering which have resulted in the generation of safe, specific, high-affinity, and non-immunogenic antibodies during the last three decades. Currently, second and third generations of antibodies are under development, mostly to improve already existing antibody specificities. However, although the refinement of already known methodologies is certainly of great importance for potential clinical use, there are no conceptually new developments in the last decade comparable, for example, to the development of antibody libraries, phage display, domain antibodies (dAbs), and antibody humanization to name a few. A fundamental question is then whether there will be another change in the paradigm of research as happened 1-2 decades ago or the current trend of gradual improvement of already developed methodologies and therapeutic antibodies will continue. Although any prediction could prove incorrect, it appears that conceptually new methodologies are needed to overcome the fundamental problems of drug (antibody) resistance due to genetic or/and epigenetic alterations in cancer and chronic infections, as well as problems related to access to targets and complexity of biological systems. If new methodologies are not developed, it is likely that gradual saturation will occur in the pipeline of conceptually new antibody therapeutics. In this scenario we will witness an increase in combination of targets and antibodies, and further attempts to personalize targeted treatments by using appropriate biomarkers as well as to develop novel scaffolds with properties that are superior to those of the antibodies now in clinical use

Remote sensing applications to hydrologic modeling in the southern Sierra Nevada and portions of the San Joaquin Valley, volume 1

The author has identified the following significant results. Characteristics of LANDSAT MSS imagery present problems in using satellite radiation measurements to estimate the shortwave albedo of an alpine snow cover. Every 15 minute USGS quadrangle contains over 100,000 pixels which poses a computation problem if each pixel is to be evaluated individually. The sampling interval may be sufficiently great to mask some effects of terrain and vegetation on reflectance. Three frames of LANDSAT imagery are needed for complete coverage of the study area, yet less than one third of the area coverage from each frame covers an area of interest. Because of distortions inherent in the imagery, information regarding spacecraft altitude, attitude, and position must be statistically derived with respect to ground control points in the image whose geodetic locations are known. An inspection of shade points indicates that up to one third of the most heavily snow covered areas may saturate in bands 4 through 6. LANDSAT's 9 day repeat cycle is not optimum for snow cover reflectance modeling because the most pronounced changes in albedo occur most nearly following a new snowfall. Such a snowfall, occurring between overpasses, is inadequately represented by extrapolation from the previous overpasses

Immunological Characterization and Neutralizing Ability of Monoclonal Antibodies Directed Against Botulinum Neurotoxin Type H.

BackgroundOnly Clostridium botulinum strain IBCA10-7060 produces the recently described novel botulinum neurotoxin type H (BoNT/H). BoNT/H (N-terminal two-thirds most homologous to BoNT/F and C-terminal one-third most homologous to BoNT/A) requires antitoxin to toxin ratios ≥1190:1 for neutralization by existing antitoxins. Hence, more potent and safer antitoxins against BoNT/H are needed.MethodsWe therefore evaluated our existing monoclonal antibodies (mAbs) to BoNT/A and BoNT/F for BoNT/H binding, created yeast-displayed mutants to select for higher-affinity-binding mAbs by using flow cytometry, and evaluated the mAbs' ability to neutralize BoNT/H in the standard mouse bioassay.ResultsAnti-BoNT/A HCC-binding mAbs RAZ1 and CR2 bound BoNT/H with high affinity. However, only 1 of 6 BoNT/F mAbs (4E17.2A) bound BoNT/H but with an affinity >800-fold lower (equilibrium dissociation binding constant [KD] = 7.56 × 10(-8)M) than its BoNT/F affinity (KD= 9.1 × 10(-11)M), indicating that the N-terminal two-thirds of BoNT/H is immunologically unique. The affinity of 4E17.2A for BoNT/H was increased >500-fold to KD= 1.48 × 10(-10)M (mAb 4E17.2D). A combination of mAbs RAZ1, CR2, and 4E17.2D completely protected mice challenged with 280 mouse median lethal doses of BoNT/H at a mAb dose as low as 5 µg of total antibody.ConclusionsThis 3-mAb combination potently neutralized BoNT/H and represents a potential human antitoxin that could be developed for the prevention and treatment of type H botulism

Geobase Information System Impacts on Space Image Formats

As Geobase Information Systems increase in number, size and complexity, the format compatability of satellite remote sensing data becomes increasingly more important. Because of the vast and continually increasing quantity of data available from remote sensing systems the utility of these data is increasingly dependent on the degree to which their formats facilitate, or hinder, their incorporation into Geobase Information Systems. To merge satellite data into a geobase system requires that they both have a compatible geographic referencing system. Greater acceptance of satellite data by the user community will be facilitated if the data are in a form which most readily corresponds to existing geobase data structures. The conference addressed a number of specific topics and made recommendations

Hidden persuaders on film: Exploring young people’s lived experience through visual essays

The Hidden Persuaders research group examines ‘brainwashing’ in the Cold War for the roles, real and imagined, played by psychologists, psychiatrists and psychoanalysts. Our project engaged young people in an exploration of the history of fears about brainwashing, and enabled them to explore their thoughts and ideas about the forces that shape their lives in contemporary society, through film-making. Working with three schools in the Camden area of London, our partners at the Derek Jarman Lab media hub, Birkbeck, University of London, and an artist facilitator (Lizzie Burns), we invited Year 12 students to learn filming and editing to create their own short video essays. The use of this format resulted in a significant depth of engagement and generated a wealth of creative responses. The various stages of the film-making process enabled the students to work out the terms of an argument and to consider how best to express it concisely. In the resulting films, they came up with a variety of forms of visual storytelling, and used the medium to express their thoughts, feelings and ideas in diverse ways, giving us a range of new perspectives which we could consider in relation to our historical research

Hypomagnesemia and increased risk of new-onset diabetes mellitus after transplantation in pediatric renal transplant recipients

Background: New onset diabetes after transplantation (NODAT) is a significant co-morbidity following kidney transplantation. Lower post-transplant serum magnesium levels have been found to be an independent risk factor for NODAT in adult kidney transplant recipients. / Methods: We undertook a retrospective analysis of risk factors for NODAT in pediatric renal transplant recipients at our institution with the aim of determining if hypomagnesemia confers a significant risk of developing NODAT in children. / Results: One hundred and seventy three children with median age at transplantation 7.0 (range: 1.3 – 17.5) years were included. Hypomagnesemia was a significant independent risk factor for NODAT (p = 0.01). High trough tacrolimus levels were also independently associated with NODAT (p < 0.001). There was no significant association between NODAT and children’s BMI at the time of transplantation, monthly cumulative steroid dose or post transplant CMV viremia (p = 0.9, 0.6 and 0.7 respectively). / Conclusions: This study identifies hypomagnesemia as a significant independent risk factor for developing NODAT in pediatric renal transplant recipients. Given the clear association between hypomagnesemia and NODAT in both adults and children following renal transplantation, further studies are merited to clarify the etiology of this association, and to examine the effect of magnesium supplementation on NODAT