Phage display-derived human antibodies in clinical development and therapy

André Frenzel, Thomas Schirrmann, Michael Hust, André Frenzel, Thomas Schirrmann, Michael Hust

Abstract

Over the last 3 decades, monoclonal antibodies have become the most important class of therapeutic biologicals on the market. Development of therapeutic antibodies was accelerated by recombinant DNA technologies, which allowed the humanization of murine monoclonal antibodies to make them more similar to those of the human body and suitable for a broad range of chronic diseases like cancer and autoimmune diseases. In the early 1990s in vitro antibody selection technologies were developed that enabled the discovery of "fully" human antibodies with potentially superior clinical efficacy and lowest immunogenicity. Antibody phage display is the first and most widely used of the in vitro selection technologies. It has proven to be a robust, versatile platform technology for the discovery of human antibodies and a powerful engineering tool to improve antibody properties. As of the beginning of 2016, 6 human antibodies discovered or further developed by phage display were approved for therapy. In 2002, adalimumab (Humira®) became the first phage display-derived antibody granted a marketing approval. Humira® was also the first approved human antibody, and it is currently the best-selling antibody drug on the market. Numerous phage display-derived antibodies are currently under advanced clinical investigation, and, despite the availability of other technologies such as human antibody-producing transgenic mice, phage display has not lost its importance for the discovery and engineering of therapeutic antibodies. Here, we provide a comprehensive overview about phage display-derived antibodies that are approved for therapy or in clinical development. A selection of these antibodies is described in more detail to demonstrate different aspects of the phage display technology and its development over the last 25 years.

Keywords: Antibody engineering; Fab; biologics; clinical development; human antibodies; phage display; recombinant antibodies; scFv; therapeutic antibodies.

Figures

Figure 1.
Figure 1.
Schema of an antibody (scFv) phage and phage display vector (phagemid) pHAL30 . Abbreviations: bla = β-lactamase, ampicillin resistance; ColE1 = bacterial origin of DNA replication; F1 IR = intergenic region of phage f1, phagemid packaging signal; gIII = phage gene encoding pIII; Lac Pro = promoter of lacZ; pIII, pVI, pVII, pVIII, pVIX = phage protein III, VI, VII, VIII, VIX; pelB = Erwinia carotovora pectate lyase B leader peptide; scFv = single chain fragment variable; VH = variable domain heavy chain; VL= variable domain light chain.
Figure 2.
Figure 2.
Schema of antibody (scFv) phage display selection, screening and reformating/production of other antibody formats (modified figure from reference 207).

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