Antibody Isotypes for Tumor Immunotherapy

Abstract

Compared to the evolutionary diversity of antibody isotypes, the spectrum of currently approved therapeutic antibodies is biased to the human IgG1 isotype. Detailed studies into the different structures and functions of human isotypes have suggested that other isotypes than IgG1 may be advantageous for specific indications - depending on the complex interplay between the targeted antigen or epitope, the desired mode of action, the pharmacokinetic properties, and the biopharmaceutical considerations. Thus, it may be speculated that with the increasing number of antibodies becoming available against a broadening spectrum of target antigens, identification of the optimal antibody isotype for particular therapeutic applications may become critical for the therapeutic success of individual antibodies. Thus, investments into this rather unexplored area of antibody immunotherapy may provide opportunities for distinction in the increasingly busy ‘antibody space'. Therefore, IgG, IgA, IgE as well as IgM isotypes will be discussed in this review.

Not all therapeutic antibody isotypes are equal: the case of IgM versus IgG in Pertuzumab and Trastuzumab

“…[4][5][6] Whilst most of the currently approved clinical monoclonal antibodies are of the IgG isotype, the high avidity of IgM and its effective complement activation and agglutination make IgM an attractive candidate for future immunotherapy. 7 Multimeric IgM exists as either ve (pentamer) or six (hexamer) subunits covalently linked to each other via disulde bridges. 8,9 Each IgM subunit is made of four polypeptide chains, namely two heavy chains containing ve immunoglobulin (Ig) domains (Cm1, Cm2, Cm3, Cm4 and VH), and two light chains comprised of two Ig domains (CL and VL) ( Fig.…”

Engineering a human IgG2 antibody stable at low pH

“…Another study demonstrated that the EGFR antibody of the human IgG2 isotype, panitumumab, mediates ADCC; however, in contrast to IgG1, the mechanism of panitumumab is limited to recruiting myeloid effector cells against EGFR‐positive tumor cells . The IgG2 subclass is predominantly selected for neutralizing antigens or inhibiting receptor‐ligand interactions . When IgG with low effector function but high resistance to acidic conditions is needed, IgG1 LALA or IgG1 N297V may be a better choice, as the disulfide isoforms of IgG2 limit the extent to which quality control is feasible .…”

Antibody Engineering - Tailor-Made Next Generation Antibodies by Molecular Design

“…To date, the IgG1 isotype is predominantly used in antibody therapy. Kretschmer et al [2] review the potential of alternative human isotypes in therapeutic application. Kellner et al [3] summarize established and emerging Fc engineering strategies, whereas Wirt and colleagues [4] analyze the potential of combining different Fc engineering strategies.…”