Bispecific antibodies: Strategies, considerations and challenges

Bispecific antibodies (BsAbs) are moving mainstream as therapeutics with currently two bispecific antibodies approved and about 30 in clinical development. The idea of using a BsAb as a therapeutic has been around for almost as long as its monospecific counterpart, however during this time over 40 MAbs were approved but only two BsAbs. One of the main reasons why BsAbs lag behind is that they are far more complex to produce. The co-expression of the two different heavy chains and two different light chains results in up to nine unwanted species in addition to the BsAb. Although a BsAb molecule can be made this way, it results in low yield and it is difficult to purify away the unwanted species. One solution to this pairing problem is to purify individual half-antibodies, combine and finally purify the bispecific antibody. The presentation will discuss novel approaches to overcome the pairing challenge and enable production in a single cell. Heavy chain mispairing is prevented by the previously established knobs-into-holes technology, while novel mutations in the antibody heavy and light chain Fab region now facilitate orthogonal pairing of the light chains. In addition, strategies to screen for the best bispecific antibody will be discussed. This includes considerations for designing bispecifics to match the proposed mechanism of action and intended clinical application

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Umsetzung der Energiestrategie 2050 - Band II : Neue Ansätze für Staat und Wirtschaft

In diesem, dem zweiten Band von "Energy Governance" befassen sich die Autoren aus vielfältiger Perspektive mit zahlreichen Fragen zur Umsetzung der Energiestrategie 2050. Sie identifizieren jene Fälle von Solaranlagen, bei denen der Ersatz einer Baubewilligung zu Rechtsunsicherheit führt. Sie untersuchen die Wirkung moderner Finanzberichterstattung auf die Politik der kantonalen Beteiligungen an Energieversorgungsunternehmen in einer Marktumgebung tiefer Strompreis. Analysiert wird weiter die staatliche Förderung der erneuerbaren Stromproduktion im Hinblick auf ihre Wirkung. Eine kritische Analyse der "Smart City"-Projekte in der Schweiz und in den Nachbarländern Deutschland und Österreich führt zu Empfehlungen, wie solche Projekte effizienter geplant und umgesetzt werden können. Auch die Beziehung öffentlicher Organisationen zu ihrer "Stakeholder-Umwelt" wird behandelt

Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease.

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (rG = 0.04) (P = 2.55 × 10-15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10-15). Our study represents a substantial advance in understanding of the genetics of PSC

Amylase MalS and protease DegP of Escherichia coli: folding and degradation under control of the temperature

In contrast to protein folding in the cytoplasm of Escherichia coli the folding of proteins in the periplasm is insufficiently examined and not well understood. Only some folding catalysts and a few specialized chaperones are identified so far. Nothing is known about the existence of a general molecular chaperone.In this work periplasmic amylase MalS was used as a model system to study the folding path and conditions of periplasmic proteins. Formation of two disulfide bonds is a prerequisite for proper folding of MalS. Disulfidebond formation is catalyzed in the periplasm by the disulfideoxidase DsbA. In absence of DsbA folding of MalS is inefficent at temperatures above 30 °C. Reduced MalS is degraded efficiently by the periplasmic protease DegP. At temperatures below 30 °C folding in absence of DsbA is much more efficient but dependent on the protease DegP. These in vivo results were completed by in vitro experiments using the purified compounds. The results revealed that protease DegP has chaperone activity at low temperatures. At elevated temperatures the protease activity is overriding the chaperone. Thus protease DegP is a bifunctional protein. As a central player it has to decide between two contrary solutions for proteins in trouble: folding or degradation