Glycoengineered Pichia produced anti-HER2 is comparable to trastuzumab in preclinical study

Mammalian cell culture systems are used predominantly for the production of therapeutic monoclonal antibody (mAb) products. A number of alternative platforms, such as Pichia engineered with a humanized N-linked glycosylation pathway, have recently been developed for the production of mAbs. The glycosylation profiles of mAbs produced in glycoengineered Pichia are similar to those of mAbs produced in mammalian systems. This report presents for the first time the comprehensive characterization of an anti-human epidermal growth factor receptor 2 (HER2) mAb produced in glycoengineered Pichia, and a study comparing the anti-HER2 from Pichia, which had an amino acid sequence identical to trastuzumab, with trastuzumab. The comparative study covered a full spectrum of preclinical evaluation, including bioanalytical characterization, in vitro biological functions, in vivo anti-tumor efficacy and pharmacokinetics in both mice and non-human primates. Cell signaling and proliferation assays showed that anti-HER2 from Pichia had antagonist activities comparable to trastuzumab. However, Pichia-produced material showed a 5-fold increase in binding affinity to FcγIIIA and significantly enhanced antibody dependent cell-mediated cytotoxicity (ADCC) activity, presumably due to the lack of fucose on N-glycans. In a breast cancer xenograft mouse model, anti-HER2 was comparable to trastuzumab in tumor growth inhibition. Furthermore, comparable pharmacokinetic profiles were observed for anti-HER2 and trastuzumab in both mice and cynomolgus monkeys. We conclude that glycoengineered Pichia provides an alternative production platform for therapeutic mAbs and may be of particular interest for production of antibodies for which ADCC is part of the clinical mechanism of action.Key words: glycoengineered Pichia, anti-HER2, trastuzumab, xenograft, PK, ADCC     

John Maynard Smith and the importance of consistency in evolutionary game theory

John Maynard Smith was the founder of evolutionary game theory. He has also been the major influence on the direction of this field, which now pervades behavioural ecology and evolutionary biology. In its original formulation the theory had three components: a set of strategies, a payoff structure, and a concept of evolutionary stability. These three key components are still the basis of the theory, but what is assumed about each component is often different to the original assumptions. We review modern approaches to these components. We emphasis that if a game is considered in isolation, and arbitrary payoffs are assumed, then the payoffs may not be consistent with other components of the system which are not modelled. Modelling the whole system, including not only the focal game, but also the future behaviour of the players and the behaviour of other population members, allows a consistent model to be constructed. We illustrate this in the case of two models of parental care, showing how linking a focal game to other aspects of the system alters what is predicted.     

Specific sensing between inositol epimers by a bis(boronate)

Bis(boronates) that utilize internal photoinduced electron transfer (PET) quenching mechanisms can specifically signal the binding of chiro-inositol without responding to its epimer, myo-inositol.     

Synaptic protein UNC-13 interacts with an F-box protein that may target it for degradation by proteasomes

UNC-13 protein participates in regulating neurotransmitter release. In Drosophila melanogaster, proteasomal degradation controls UNC-13 levels at synapses. Function of the amino-terminal region of a 207 kDa form of Caenorhabditis elegans UNC-13 is unknown. Yeast two-hybrid and secondary yeast assays identified an F-box protein that interacts with this amino-terminal region. As F-box proteins bind proteins targeted for proteasomal degradation, this protein may participate in degrading a subset of UNC-13 proteins, suggesting that different forms of UNC-13 are regulated differently. Yeast assays also identified an exonuclease, a predicted splicing factor, and a protein with coiled-coil domains, indicating that UNC-13 may affect RNA function.     

The cholecystokinin type A receptor g.179A>G polymorphism affects feeding rate

A polymorphism within the 5' untranslated region of the cholecystokinin type A receptor ( CCKAR ) gene has been shown to affect feed intake and growth in commercial pig lines. To further investigate the phenotype of animals carrying alternative alleles at this polymorphism, we genotyped animals from a distinct segregating commercial line and an experimental cross F₂ population, both with electronically recorded feeding pattern data. The data indicate that the daily feed intake increasing effect of the DQ496228:g.179G allele is mediated through a faster rate of feed intake, without evidence for an effect on other feeding behaviour traits.