IgA
Another rather promising Ig isotype for tumour-depleting mAbs is IgA, which mediates its effector functions through FcαRI. The FcαRI induces activating signals when IgA is encountered as an immune complex, however, induces inhibitory signals upon monomeric binding49,50. FcαRI is highly expressed on polymorphonuclear cells (PMNs), making neutrophils the most relevant cell type for IgA mAb therapy. Neutrophils represent the most abundant cytotoxic cell type in humans. They are armed with a variety of potent cell destruction mechanisms, including the release of cytotoxic molecules, induction of apoptosis and necrosis. Furthermore, they are well established for their recruitment of other immune cells and phagocytosis49,51. Importantly, it has been shown that, compared to cross-linking of FcγR, FcαRI cross-linking is far more efficient in the activation of neutrophils51–53.
However, in vivo studies are still scarce, largely due to the fact that mice lack a FcαR homolog. Creation of a transgenic human FcαR mouse strain54 allowed in vivo studies in which the anti-tumoural effect of IgA antibodies was demonstrated55,56. Surprisingly, macrophages were shown to be the crucial effector population for anti-EGFR IgA in vivo , leaving the role of neutrophils unclear. Unfortunately, the transgenic hFcαR mouse only partially resolved the lack of a useful model, as human IgA has a very short half-life in mice. Therefore, hIgA mouse pharmacokinetics and exposure were enhanced by attaching an albumin-binding domain to improve FcRn binding and thus the recycling of the antibody57. Furthermore, by Fc-engineering the clearance by the asialoglycoprotein receptor in the liver could be reduced58. In both cases, increased IgA half-life translated into improved anti-tumour efficacy in mouse models.These strategies may direct more extensive exploration of IgA-based cancer therapies in murine models and might be considered for extending the relatively short serum half-life of IgA mAbs in humans.
Similar to IgG1/IgG3 chimeras, IgG1/IgA chimera has been constructed with the intention of combining the advantages of the two different isotypes. Its binding to FcRn, FcγRs and C1q provided the IgG1/IgA chimera with an extended half-life and the capability to activate macrophages and complement, respectively. Furthermore, the additional FcαR binding of this chimeric antibody construct initiated recruitment of neutrophils, resulting in an overall improved cytotoxicity59. Thus, the combined effector functions of such chimeric isotype mAb construct may further improve the clinical efficacy of tumour-targeting mAbs.