Recombinant Human Antibody Therapeutics: Supply Strategies for Early and Clinical Development from CHO Cells

摘要

Human antibody therapeutics are effective tools in the treatment of serious diseases. Isolation of human antibodies using display technologies combined with rapid reformatting methods allow the ability to screen for those antibody variants that exhibit high level of expression in the preferred IgG format. Alteration of the IgG gene can also markedly improve expression, e.g. removal of unwanted cryptic splice sites, and when coupled with process optimisation transient IgG expression titres of ~ 100 mg/L from suspension CHO cells are achievable at >10 L scale in a wavebag bioreactor. Such strategies allow early evaluation of multiple IgG constructs in vitro and in vivo by facilitating production of gram amounts of IgG from CHO cells prior to stable cell construction.The use of the Glutamine Synthetase expression system (GS System~(TM), licensed from Lonza Biologies) in CHO cells allows the isolation of either parental cell lines or pools of cells. Both are often sufficiently stable for scale up in a platform process to produce 10-100+g batches of IgG at an early stage for use as a reference standard, pharmacology or other drug characterisation studies (e.g. formulation).At CAT, supply of therapeutic IgG for clinical evaluation has been carried out using both GS-NSO and GS-CHO clonal cell lines, the CHO system appears less resource intensive and with more potential for process improvement. Development of generic platform fed-batch fermentation processes has led to fermentation titles in the 1-3 g/L range for early clinical development.