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.