Administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons

The efficiency of first-generation adenoviral vectors as gene delivery tools is often limited by the short duration of transgene expression, which can be related to immune responses and to toxic effects of viral proteins. In addition, readministration is usually ineffective unless the animals are immunocompromised or a different adenovirus serotype is used. Recently, adenoviral vectors devoid of all viral coding sequences (helper-dependent or gutless vectors) have been developed to avoid expression of viral proteins. In mice, liver-directed gene transfer with AdSTK109, a helper-dependent adenoviral (Ad) vector containing the human α1-antitrypsin (hAAT) gene, resulted in sustained expression for longer than 10 months with negligible toxicity to the liver. In the present report, we have examined the duration of expression of AdSTK109 in the liver of baboons and compared it to first- generation vectors expressing hAAT. Transgene expression was limited to approximately 3-5 months with the first-generation vectors. In contrast, administration of AdSTK109 resulted in transgene expression for longer than a year in two of three baboons. We have also investigated the feasibility of circumventing the humoral response to the virus by sequential administration of vectors of different serotypes. We found that the ineffectiveness of readministration due to the humoral response to an Ad5 first-generation vector was overcome by use of an Ad2-based vector expressing hAAT. These data suggest that long-term expression of transgenes should be possible by combining the reduced immunogenicity and toxicity of helper-dependent vectors with sequential delivery of vectors of different serotypes

Performance guarantees and optimal purification decisions for engineered proteins

We investigate protein purification operations conducted by biomanufacturers and pharmaceutical companies as part of their research and development efforts. Purification of these proteins involves unique challenges such as balancing the yield and purity trade-offs, dealing with uncertainty in the starting material, and estimating the impact of several interlinked decisions.We develop a Markov decision model and partition the state space into decision zones that provide managerial insights to optimize purification operations. We develop practical guidelines to quantify financial risks, and we characterize the optimal operating decisions based on specific production requirements. The optimization framework has been implemented at Aldevron, a contract biomanufacturer specializing in proteins, and has resulted in 25% reduction in the total lead times and 20% reduction in the costs of protein purification operations on average

Aldevron accelerates growth using operations research in biomanufacturing

In the biomanufacturing industry, production and planning decisions are often challenging because of batch-to-batch variability and uncertainty in the production yield, quality, cost, and lead times. To improve biomanufacturing efficiency, a multidisciplinary team of researchers collaborated over five years to develop a portfolio of decision support tools. The tools developed provide a data-driven, operations research–based approach to reduce biomanufacturing costs and lead times. These decision support tools comprise multiple deterministic and stochastic optimization models to optimize production and planning decisions. To optimize production decisions related to fermentation and protein purification, optimization tools were developed to provide a decision support mechanism that links the underlying biological and chemical processes with business risks and financial trade-offs. To optimize planning decisions, interactive scheduling and capacity planning tools were developed to enable efficient use of expensive and limited resources. Although developed in collaboration with Aldevron, these tools address common industry challenges, and they have been shared with a wider industry community through working group sessions