Fc Engineering Strategies to Advance IgA Antibodies as Therapeutic Agents

Abstract

In the past three decades, a great interest has arisen in the use of immunoglobulins as therapeutic agents. In particular, since the approval of the first monoclonal antibody Rituximab for B cell malignancies, the progress in the antibody-related therapeutic agents has been incremental. Therapeutic antibodies can be applied in a variety of diseases, ranging from cancer to autoimmunity and allergy. All current therapeutic monoclonal antibodies used in the clinic are of the IgG isotype. IgG antibodies can induce the killing of cancer cells by growth inhibition, apoptosis induction, complement activation (CDC) or antibody-dependent cellular cytotoxicity (ADCC) by NK cells, antibody-dependent cellular phagocytosis (ADCP) by monocytes/macrophages, or trogoptosis by granulocytes. To enhance these effector mechanisms of IgG, protein and glyco-engineering has been successfully applied. As an alternative to IgG, antibodies of the IgA isotype have been shown to be very effective in tumor eradication. Using the IgA-specific receptor FcαRI expressed on myeloid cells, IgA antibodies show superior tumor-killing compared to IgG when granulocytes are employed. However, reasons why IgA has not been introduced in the clinic yet can be found in the intrinsic properties of IgA posing several technical limitations: (1) IgA is challenging to produce and purify, (2) IgA shows a very heterogeneous glycosylation profile, and (3) IgA has a relatively short serum half-life. Next to the technical challenges, pre-clinical evaluation of IgA efficacy in vivo is not straightforward as mice do not naturally express the FcαR. Here, we provide a concise overview of the latest insights in these engineering strategies overcoming technical limitations of IgA as a therapeutic antibody: developability, heterogeneity, and short half-life. In addition, alternative approaches using IgA/IgG hybrid and FcαR-engagers and the impact of engineering on the clinical application of IgA will be discussed.

Avidity in antibody effector functions and biotherapeutic drug design

“…There has been a steady increase of studies detailing the engineering and clinical translation of naturally multivalent immunoglobulin isotypes such as IgM and IgA, despite being more challenging to develop than IgGs owing to their more complex multichain architectures, more extensive and heterogeneous glycosylation patterns and shorter in vivo half-lives 38 , 167 , 168 . In a unique ocular application, Agard and colleagues used the multivalent nature of IgM to effectively agonize the tyrosine-protein kinase receptor TIE2; this application capitalized on the large size of IgM to reduce vitreal clearance, which was shown to be inversely proportional to the molecule’s hydrodynamic radius 169 .…”

Expression of mammalian proteins for diagnostics and therapeutics: a review

“…Human immunoglobulin isotypes consist of IgA, which subtypes to IgA1 and IgA2, IgD, IgE, IgG that subtypes to IgG1, IgG2, IgG3, and IgG4, as well as IgM. IgG is the leading molecular format used in today’s antibody drugs as it neutralizes infectious mediums and engage immune cells by activating the complement system [ 37 , 40 ]. In preclinical stages, there are more non-IgG formats used although IgG is still the most dominant despite this, interest in testing alternative CH variants as therapeutic antibodies is growing [ 41 ].…”

“…IgM also exhibits specialised immune functions besides possessing higher avidity and steric hindrance, which neutralizes viruses as well as serving as the primary antibody defence against new antigens [ 37 , 43 , 44 ]. Furthermore, early clinical studies have introduced the potential of IgA isotype antibodies as anti-cancer therapeutics as it can reduce tumours [ 40 ]. Additionally, IgE antibody molecules, despite being the least abundant CH variant, can utilize FcRs from monocytes and macrophages to activate different effector cell population which defines its role in allergy and parasitic infections [ 45 ].…”

The Functional Role of IgA in the IgM/IgA-Enriched Immunoglobulin Preparation Trimodulin

“…Despite its high abundancy, knowledge concerning the functional role of serum IgA is not adequate. The reasons are: (1) limitations in animal models (e.g., for rodents: missing FcαRI, polymeric IgA molecule instead of monomeric IgA in human); (2) recombinant production of IgA is difficult by the high and heterogeneous glycosylation; and (3) the low stability as well as the short serum half-life compared to IgG [5,[10][11][12][13].…”