Design out Gal-α(1,3)-Gal for biobetter MAbs

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Design out Gal-α(1,3)-Gal for biobetter MAbs

Biosimilars/Research | Posted 28/01/2010 0 Post your comment

In an article by Dr Claire Morgan and Dr Daryl Fernandes of Ludger, published in IPI of Autumn 2009, it is shown how both the original drug manufacturers and the designers of follow-on biologics could produce biobetter monoclonal antibodies (MAbs) through glycoengineering. (see also Ludger’s GTO-QbD: Defining glycovariant biobetter MAbs, When is a glycoengineered biobetter commercially better than a biosimilar? and Strategy and tools for building glycoengineered biobetter MAbs)

Dr Morgan and Dr Fernandes suggest several first glycosylation features to consider modifying when designing biobetter MAbs. These include changes to the N-glycans in the Cg2 domain of the fragment crystallisable (Fc) region, as well as modifications to fragment antigen-binding (Fab) glycans if they exist in the therapeutic. In general, major changes can be achieved by switching cell lines, and smaller changes by modifying cell culture conditions. They note that the modification of one glycosylation feature will generally affect others, so when glycoengineering the glycosylation should be viewed as a whole, rather than the sum of independent components. (see also Design out NeuGc, Fab glycosylation for biobetter MAbs and Modify Fc fucosylation and β-galactosylation for biobetter MAbs)

Design out Gal-α(1,3)-Gal

As explained by the authors, Gal-α(1,3)-Gal is an undesirable non-human disaccharide found on the glycans of some MAbs, particularly those expressed in mouse-derived cell lines. Immune reactions to Gal-α(1,3)-Gal are responsible for tissue rejection in xenotransplantation and the disaccharide has been shown to be directly recognised by natural killer (NK) cells. All humans have Immunoglobulin G (IgG) antibodies specific to the oligosaccharide Gal-α(1,3)-Gal, which is closely related to substances in the ABO blood group. Anti-Gal-α(1,3)-Gal Immunoglobulin E (IgE) antibodies are found in high levels in some individuals who can show severe hypersensitivity reactions if treated with MAbs containing Gal-α(1,3)-Gal units on their glycans. Such anaphylactic reactions have been found in some patients treated with a form of the anticancer drug Cetuximab that was produced in a mouse cell and which contained high levels of Gal-α(1,3)-Gal in the glycans on asparagine (Asn)-88 of the Fab portion of the antibody heavy chain. According to Dr Morgan and Dr Fernandes, Gal-α(1,3)-Gal can be designed out by switching to a non-mouse cell line, but they advise to still check for low level presence of the disaccharide after the switch. Eliminating this disaccharide should give a biobetter with a better safety and/or efficacy profile.

Reference:

Claire Morgan and Daryl Fernandes. Designing Biobetter Monoclonal Antibody Therapeutics By Glycoengineering. International Pharmaceutical Industry (IPI) p. 38-44. Autumn 2009.

Source: International Pharmaceutical Industry (IPI)