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    Mentor  Pharmaceutical Consulting


 
 

Oral Delivery of IgG

The use of monoclonal antibodies (MAbs) in therapy in humans has made them the fastest growing protein pharmaceutical, with anti-TNF molecules the largest of the group, with total sales in 2008 of US$16.4 bln. One product alone, Enbrel had sales of $6.4 bln., which was higher than the next highest biological interferon beta (US$ 5.4 bln).

 According to LaMere, addressing the issue of Monoclonal Antibodies: 2010 “Across the branded prescription pharmaceutical market monoclonal antibodies (MAbs) are forecast to be the strongest performing molecule type, delivering a forecast six year compound annual growth rate of 9.5% over 2009-15, outpacing the growth rates of small molecules, therapeutic proteins and vaccines. As a result, there is a strong correlation between a strong MAb portfolio and overall company?

 Administration of anti-TNF molecules is generally by subcutaneous injection either once or thrice weekly, depending upon the molecule and dose, as it is thought that these molecules have a very low bioavailability when given via other routes. Despite this there are obvious benefits to oral delivery of the molecules, including the ability to maintain a flatter serum profile for the anti-TNF, an increase in patient comfort, an increase in patient compliance, and the possibility of achieving site directed targeting to the intestinal wall, the site of conditions such as Crohn’s disease.

Immunity in the new-born of many species is passively acquired from antibodies present in the mother’s milk, more particularly the colostrum. These ingested antibodies, primarily of the IgG class, bind to a specific receptor, the IgG-Fc receptor (FcRn), on the intestinal wall, and are transported across the intestinal epithelial barrier, in an apical to basal fashion via the FcRn receptor, and eventually end up in serum. The FcRn transport system has very high capacity and hence the amount of IgG transported in the neonate is very high. Thus cattle, which  produce around 10 kg of colostrum per day in which the IgG ranges from 25-30 mg/kg (first milking) to 2 mg/kg by day 6 are able to achieve a total uptake over 6 days of around 500-700 mg IgG1 into the neonatal calf.

Binding of IgG to the FcRn is pH dependent with binding occurring below pH 7.0, and the IgG being released once the pH rises above pH 7.0 in the circulation (Ghetie et al, 1997; Ober et al, 2004). Thus the IgG binds to the receptor in the acid milieu of the intestine, remains associated with the receptor whilst in the acidic compartments within the cell and is released at the neutral pH of the interstitial space. Once the IgG is lost from the receptor, the receptor recycles to the apical surface of the epithelial cell where it can pick up more IgG for transport.

Initially, it was thought that the neonatal receptor was lost following weaning and was absent in adult life (mainly from studies in rats, Dickinson et al, 1999; Rodewald, 1980). More recently it has been shown that the receptor is present in the intestine of adult human and non-human primates as well as being present on the epithelial cells of human lung and kidney cells and rat hepatocytes (Blumberg et al, 1995; Israel et al, 1997; Haymann et al, 2000; Spiekermann etal, 2002; Dickinson et al, 1999; Stirling et al, 2005; Rojas and Apodaca, 2002; Roopenian and Akilesh, 2007). Additionally, the FcRn has been found to be responsible for transplacental transfer of IgG in humans (Story et al, 1994). Dickinson and co-workers (1999) have found that the FcRn is expressed in the human polarized intestinal cell line, T84 and is able to transport IgG in vitro. FcRn mediated apical to basal transport of IgG-Ag complexes has also been shown in MDCK cells (Yoshida etal, 2004).

FcRn has important effects on IgG-mediated mucosal immunity and host defense in adult intestines. It has also been demonstrated that IgG is present in secretions of the human mucous membranes such as oral mucosa, lung, intestine, and genitourinary tract. Intestinal washout studies have shown that at least in mice (the only species tested), whole IgG tends to remain intact in the mucous blanket overlying the intestinal mucosa, with little being found in the intestinal lumen.

Identification of the Fc receptor (FcRn) on the epithelial cells of adult human lung and intestine has led to studies to examine the possibility of using this receptor as a transporter for peptide and protein delivery. Efforts have mainly focused on the production of Fc-protein fusions and their use for pulmonary delivery of these fusions under the belief that successful oral delivery would not be possible due to the high levels of proteolysis in the gut

Work by Dr Russell-Jones and associates has shown that in fact it is possible to use the natural intestinal FcRn mediated transport for oral uptake of IgG1 MAbs, strongly suggesting that this system, which has been identified to be present in post-natal/adult humans, could be used as a transport system for oral delivery of the vast number of human IgG1 monoclonal antibodies currently in the clinic. In addition it has application to the numerous Fc-fusion complexes of effector molecules, such as soluble cytokine receptors and growth factors that have been coupled to the Fc domain of IgG1, with retention of their biological activities.

IgG normally excreted into, or administered to, the intestine is clipped by the intestinal enzyme, trypsin, at one of the many tryptic cleavage sites around the centre of the IgG molecule. Oral vaccination leads to the generation of an IgG response in the sub-epithelial B cells, which secrete IgG, and is carried via the FcRn into the intestine. Once it has reached the mucous blanket it is protected from tryptic cleavage as the trypsin is present in the lumen of the intestine rather than the mucous. Isolation of such mucous reveals the presence of significant levels of specific IgG, which can be recovered from the intestine of orally vaccinated mice (Russell-Jones et al 1983). Mentor has developed a system specifically designed to minimize enzymatic cleavage of IgG1, thereby allowing for maximal uptake of orally administered IgG1

Histological Demonstration of the IgG-FcRn in adult mouse intestine

Experiments with  FITC-IgG1or  Rho-IgG1have demonstrated functional FcRn in mouse small intestine

Binding of FITC-IgG to GIT epithelium
Nuclei Stained blue

Binding of Rho-IgG to GIT epithelium

Demonstration of the anti-inflammatory activity of orally administered anti-TNF

It is well known that oral administration of IgG1 results in cleavage of the Fab/Fc hinge region to yield material that is not systemically bioavailable. As can be seen below orally administered anti-TNF, when administered without enzymatic protection shows no reduction in inflammation in the carrageenan mouse model of inflammation (Left Panel). It is possible, however, to use special excipients, which when co-administered, or mixed with the IgG protect it from proteolysis and allow the Fc fragment to still bind to the FcRn in the intestine and thereby make the IgG systemically bioavailable. Thus, oral administration of anti-TNF protected using oral monoclonal technology (OMT) is highly active in reducing inflammation in the inflammatory model (right panel)

 

 

Summary

Oral administration of unprotected IgG results in cleavage of the IgG by small intestinal enzymes. In contrast co-feeding or co-formulation of IgG using polymers that associate with the hinge region of the IgG, yields material that is highly bioavailable, as judged by the reduction in foot pad inflammation. This simple method has application to the vast majority of IgG1 monoclonal antibodies, or IgG1-Fc fusion proteins.

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