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

HIV-1 infection of cells and AIDS progression

HIV-1, the etiological agent of AIDS, enters cells within minutes after binding to a receptor molecule, fusing its membrane with the cell membrane and uncoating its envelope to deliver the RNA-protein complex into the cell cytoplasm. The infection cycle then proceeds for hours to days through a series of steps, including reverse transcription of the viral RNA, integration of the resulting DNA into the cellular genome, transcription of the proviral DNA, expression of virus proteins, their assembly and virus budding, leading to production of progeny virions. Virus spread by subsequent cycles of infection occurs within weeks and months, while AIDS develops after years or even decades. This review discusses the causes of this diversity in kinetics, emphasizing the importance of quantitation, and how quantitation of infection kinetics may help in understanding the factors that affect the disease progression.Biomedical Reviews 1993; 2: 1-8

MWERA 2007 Highlights

Annual Meeting Highlight

Contemporary Treatment of Reliability and Validity in Educational Assessment

MWERA 2009 Presidential Addres

Multimethod Analysis of Mathematics Achievement Tests

Multimethod analysis of mathematics achievement tests is illustrated by combining psychometric and statistical methods in the analysis of results from the California Achievement Test-Mathematics administered to seventh-graders from North-East Ohio

Summer Preview of the 2007 Annual Meeting October 24-27, 2007

Summer Preview of the Annual Meetin

Mid-Western Educational Research Association 2007 Annual Meeting, October 24-27, 2007

Call for Proposal

The SARS Coronavirus S Glycoprotein Receptor Binding Domain: Fine Mapping and Functional Characterization

The entry of the SARS coronavirus (SCV) into cells is initiated by binding of its spike envelope glycoprotein (S) to a receptor, ACE2. We and others identified the receptor-binding domain (RBD) by using S fragments of various lengths but all including the amino acid residue 318 and two other potential glycosylation sites. To further characterize the role of glycosylation and identify residues important for its function as an interacting partner of ACE2, we have cloned, expressed and characterized various soluble fragments of S containing RBD, and mutated all potential glycosylation sites and 32 other residues. The shortest of these fragments still able to bind the receptor ACE2 did not include residue 318 (which is a potential glycosylation site), but started at residue 319, and has only two potential glycosylation sites (residues 330 and 357). Mutation of each of these sites to either alanine or glutamine, as well as mutation of residue 318 to alanine in longer fragments resulted in the same decrease of molecular weight (by approximately 3 kDa) suggesting that all glycosylation sites are functional. Simultaneous mutation of all glycosylation sites resulted in lack of expression suggesting that at least one glycosylation site (any of the three) is required for expression. Glycosylation did not affect binding to ACE2. Alanine scanning mutagenesis of the fragment S319–518 resulted in the identification of ten residues (K390, R426, D429, T431, I455, N473, F483, Q492, Y494, R495) that significantly reduced binding to ACE2, and one residue (D393) that appears to increase binding. Mutation of residue T431 reduced binding by about 2-fold, and mutation of the other eight residues – by more than 10-fold. Analysis of these data and the mapping of these mutations on the recently determined crystal structure of a fragment containing the RBD complexed to ACE2 (Li, F, Li, W, Farzan, M, and Harrison, S. C., submitted) suggested the existence of two hot spots on the S RBD surface, R426 and N473, which are likely to contribute significant portion of the binding energy. The finding that most of the mutations (23 out of 34 including glycosylation sites) do not affect the RBD binding function indicates possible mechanisms for evasion of immune responses

Group Comparisons on Cognitive Attributes Using the Least Squares Distance Model of Cognitive Diagnosis

2010 Mathematics Subject Classification: 62P15.As the cognitive operations are hypothesized according to a cognitive theory in the context of a study, they are latent (hidden) in nature and cannot be measured and scored directly from the test. The least squares distance model (LSDM) of cognitive diagnosis uses estimates of the item parameters under a specific item-response theory (IRT) model to provide estimates of the probability of a person to process correctly any cognitive attribute given the person’s location on the IRT logit scale. In this paper a methodology for comparing two (or more) groups of individuals, according to their performance on a given set of cognitive attributes is presented

Psychometric Features of the General Teacher Test under the D-Scoring Model: The Case of Teacher Certification Assessment in Saudi Arabia

The teachers’ knowledge and skills on general standards under the Saudi National Professional Teacher Standards is assessed with the use of the General Teacher Test (GTT) administered by the National Center for Assessment (NCA) in Saudi Arabia. This paper examines the psychometric features of the GTT in the framework of a new approach to test scoring, referred to as D-scoring model, which is used with assessments at the NCA. The stability of such features across four test forms of the GTT is also examined. The study findings provide valuable information about the accuracy of the GTT scores and the validity of their interpretation and decisions regarding the licensure of teachers