Advances in Mammalian Cell Line Development Technologies for Recombinant Protein Production

TLDR

The rapid approval of recombinant protein therapeutics and the rise of biosimilars have increased demand for high‑productivity mammalian cell lines, yet current MTX and GS systems generate heterogeneous clones that require extensive screening, making the development process 6–12 months long and resource intensive. This review aims to evaluate advances in protein expression and clone‑screening technologies to accelerate and improve the efficiency of generating robust, highly productive cell lines for large‑scale therapeutic protein production. The authors survey established advances in protein expression and clone‑screening methods that constitute the core technologies of mammalian cell line development.

Abstract

From 2006 to 2011, an average of 15 novel recombinant protein therapeutics have been approved by US Food and Drug Administration (FDA) annually. In addition, the expiration of blockbuster biologics has also spurred the emergence of biosimilars. The increasing numbers of innovator biologic products and biosimilars have thus fuelled the demand of production cell lines with high productivity. Currently, mammalian cell line development technologies used by most biopharmaceutical companies are based on either the methotrexate (MTX) amplification technology or the glutamine synthetase (GS) system. With both systems, the cell clones obtained are highly heterogeneous, as a result of random genome integration by the gene of interest and the gene amplification process. Consequently, large numbers of cell clones have to be screened to identify rare stable high producer cell clones. As such, the cell line development process typically requires 6 to 12 months and is a time, capital and labour intensive process. This article reviews established advances in protein expression and clone screening which are the core technologies in mammalian cell line development. Advancements in these component technologies are vital to improve the speed and efficiency of generating robust and highly productive cell line for large scale production of protein therapeutics.