Transgenic mice human monoclonal antibodies

Human monoclonal antibodies are made either by hybridomas from transgenic mice that have had their mouse antibody genes replaced with human antibody genes, or by a process called phage display. Human monoclonal antibodies end with the suffix -mumab. The first human monoclonal antibody developed through phage display technologies was adalimumab (Humira), which was approved by the FDA to treat several immune system diseases. 

Siegel, S.A. et al., The mouse/human chimeric monoclonal antibody cA2 neutralizes TNF in vitro and protects transgenic mice from cachexia and TNF lethality in vivo, Cytokine, 7, 26, 1995. 

A further advance in antibody technology is the development of transgenic mouse human strains. XenoMouse animals have been engineered in such a way that they now produce exclusively human antibodies rather than murine antibodies when immunized. The use of XenoMouse animals to produce MAbs avoids the need for any engineering of the antibody genes, since the products are already 100% human protein. XenoMouse animals are fully compatible with standard hybridoma technology and can be readily adopted by laboratories experienced in monoclonal antibody production [56]. 

Therapeutic monoclonal antibodies are widely recognized to be a most promising means to treat an increasing number of human diseases, including cancers and autoimmunity. To a large extent, the efficacy of monoclonal antibody treatment is because IgG antibodies have greatly extended persistence in vivo. However, conventional rodent models do not mirror human antibody pharmacokinetics. The key molecule responsible for the extended persistence antibodies is the major histocompatibility complex class I family Fc receptor, FcRn. We describe human FcRn transgenic mouse models and how they can be exploited productively for the preclinical pharmacokinetic evaluation of therapeutic antibodies. 

Fig. 1. Binding of protein L to human B cells and to mouse B cells expressing human Igs. a Human peripheral blood lymphoid cells were stained with FITC-labeled anti-human CD 19 monoclonal antibody and biotinylated protein L, followed by Cy-chrome-labeled streptavidin. b Splenic cells from transgenic mice expressing human Igs [46] were stained with FITC-labeled anti-mouse B220 monoclonal antibody and biotinylated protein L, followed by Cy-chrome-labeled streptavidin. All monoclonal antibodies and their corresponding isotype controls were purchased from BD PharMingen.

Fig. 2. Repeated injections of protein A deplete B-la cells in the PeC. Transgenic Xenomouse mice expressing human Igs [17] were injected intraperitoneally with 0 (open bars), 125 (gray bars), 250 (stippled bars) or 500 p,g (black bars) of recombinant protein A. After 24 h, peritoneal cells were washed and then cells were triple stained with fluorescent antibodies to human IgM (G20-127), mouse CD1 lb (Ml/70), and mouse CD5-PE (53-7.3). FACS analysis allowed identification of the B-la (IgM+CDl lb+CD5+) and B-lb cell subsets (IgM+CDllb+CD5—). All monoclonal antibodies and their corresponding isotype controls were purchased from BD PharMingen. p < 0.05. 

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