An anti-EGFR IgA that displays improved pharmacokinetics and myeloid effector cell engagement in vivo

Antibodies of IgA isotype effectively engage myeloid effector cells for cancer immunotherapy. Here, we describe pre-clinical studies with an Fc engineered IgA2m(1) antibody containing the variable regions of the EGFR antibody cetuximab. Compared to wild type IgA2m(1), the engineered molecule lacked two N-glycosylation sites (N166, N337), two free cysteines (C311, C472) and contained a stabilized heavy and light chain linkage (P221R mutation). This novel molecule displayed improved production rates and biochemical properties compared to wild type IgA. In vitro, Fab- and Fc-mediated effector functions such as inhibition of ligand binding, receptor modulation and engagement of myeloid effector cells for antibody-dependent cell-mediated cytotoxicity were similar between wild type and engineered IgA2. The engineered antibody displayed lower levels of terminal galactosylation leading to reduced asialoglycoprotein-receptor binding and to improved pharmacokinetic properties. In a long-term in vivo model against EGFR-positive cancer cells, improved serum half-life translated into higher efficacy of the engineered molecule, which required myeloid cells expressing human FcαRI for its full efficacy. However, Fab-mediated effector functions contributed to the in vivo efficacy since the novel IgA antibody demonstrated therapeutic activity also in non-FcalphaRI transgenic mice. Together, these results demonstrate that engineering of an IgA antibody can significantly improve its pharmacokinetics and its therapeutic efficacy to inhibit tumor growth in vivo.

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