Improved in vivo anti-tumor effects of IgA-Her2 antibodies through half-life extension and serum exposure enhancement by FcRn targeting

Abstract

Antibody therapy is a validated treatment approach for several malignancies. All currently clinically applied therapeutic antibodies (Abs) are of the IgG isotype. However, not all patients respond to this therapy and relapses can occur. IgA represents an alternative isotype for antibody therapy that engages FcαRI expressing myeloid effector cells, such as neutrophils and monocytes. IgA Abs have been shown to effectively kill tumor cells both in vitro and in vivo. However, due to the short half-life of IgA Abs in mice, daily injections are required to reach an effect comparable to IgG Abs. The relatively long half-life of IgG Abs and serum albumin arises from their capability of interacting with the neonatal Fc receptor (FcRn). As IgA Abs lack a binding site for FcRn, we generated IgA Abs with the variable regions of the Her2-specific Ab trastuzumab and attached an albumin-binding domain (ABD) to the heavy or light chain (HCABD/LCABD) to extend their serum half-life. These modified Abs were able to bind albumin from different species in vitro. Furthermore, tumor cell lysis of IgA-Her2-LCABD Abs in vitro was similar to unmodified IgA-Her2 Abs. Pharmacokinetic studies in mice revealed that the serum exposure and half-life of the modified IgA-Her2 Abs was extended. In a xenograft mouse model, the modified IgA1 Abs exhibited a slightly, but significantly, improved anti-tumor response compared to the unmodified Ab. In conclusion, empowering IgA Abs with albumin-binding capacity results in in vitro and in vivo functional Abs with an enhanced exposure and prolonged half-life.

IgA: Structure, Function, and Developability

“…This shorter half-life is in part due to clearance mediated by the ASGPR, which recognises terminal galactose residues on the glycans of IgA. Efforts have been made to extend half-life by removing N-linked glycosylation sites [139], generating IgA with higher terminal sialylation of N-glycans [140], by attaching an albumin-binding domain to either the LC or HC in order to facilitate binding to the neonatal Fc receptor FcRn [141], or by engineering in FcRn binding by generating an IgG-IgA Fc fusion [133].…”

Serum IgA Fc effector functions in infectious disease and cancer

“…Furthermore, technologies available for the expression and purification of IgA (especially dIgA/pIgA) are comparatively more complicated than IgG . However, modifications to IgA mAb can improve half‐life and stability . Combinations of IgG and IgA mAbs can enhance tumor killing and work on “cross‐type antibodies” such as IgGA and tandem antibodies combines the best of both IgG (complement binding) and IgA (cytotoxicity/phagocytosis) antitumor effects …”

Neutrophils in cancer

“…Another option that has been suggested is to generate IgA mAbs which are attached to an albumin‐binding domain. Binding to albumin extended the half‐life of the IgA antibodies and also slightly improved their anti‐tumor activity . Finally, an IgGA antibody has been developed that has the capacity to bind to both FcγRs and FcαRI .…”