Antibody therapeutics: isotype and glycoform selection.
Recombinant monoclonal antibody (rMAb) therapy may be instituted to achieve one of two broad outcomes: i) killing of cells or organisms (e.g., cancer cells, bacteria); and ii) neutralisation of soluble molecules (e.g., cytokines in chronic disease or toxins in infection). The choice of rMAb isotype is a critical decision in the development of a therapeutic antibody as it will determine the biological activities triggered in vivo. It is not possible, however, to accurately predict the in vivo activity because multiple parameters impact on the functional outcome, for example, IgG subclass, IgG-Fc glycoform, epitope density, cellular Fc receptors polymorphisms and so on. The present understanding of the molecular interactions between IgG-Fc and effector ligands in vitro has allowed the generation of new antibody structures with altered/improved effector function profiles that may prove optimal for given disease indications. Thus, when maximal antibody-dependent cell-mediated cytotoxicity activity is indicated a non-fucosylated IgG1 format may be optimal; when minimal activity is indicated an aglycosylated IgG2 may be the form of choice.
Jefferis
Roy
R
University of Birmingham, Division of Immunity & Infection, The School of Medicine, Edgbaston, Birmingham B15 2TT, UK. R.Jefferis@bham.ac.uk
D000911:Antibodies, Monoclonal / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000235:genetics; D005643:Fucose / Q000378:metabolism / Q000627:therapeutic use*; D006031:Glycosylation; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology*; D007132:Immunoglobulin Isotypes / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D017452:Receptors, IgG / Q000502:physiology*
D000911:Antibodies, Monoclonal; D007141:Immunoglobulin Fc Fragments; D007132:Immunoglobulin Isotypes; D017452:Receptors, IgG; D005643:Fucose