Engineering IgA for cancer therapy with neutrophils
Therapeutic antibodies can be applied for a variety of diseases. Strikingly, 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 effective in tumor eradication. Using the FcαRI (CD89) expressed on myeloid cells, IgA antibodies show superior tumor-killing compared to IgG when granulocytes are employed as effector cells.
However, reasons why IgA has not been introduced in the clinic yet can be found in the intrinsic properties of IgA which poses several technical limitations: (1) IgA is challenging to produce and purify, (2) IgA shows a heterogeneous glycosylation profile, and (3) IgA has a relatively short plasma half-life. Next to the technical challenges, pre-clinical evaluation of IgA efficacy in vivo is not straightforward as mice do not naturally express FcaRI. In the presentation, I will provide a concise overview of the latest insights in engineering strategies to overcome the technical limitations of IgA as a therapeutic antibody. In addition, I will show how to engage myeloid-derived suppressor cells against cancer using IgA, elucidate on the key cytokines for IgA antibody therapy in vitro and in vivo and will conclude with IgA for the treatment of neuroblastoma using GD2 as a target.