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Abstract
Antibodies of IgA isotype effectively engage myeloid effector cells for cancer immunotherapy. Here, we describe preclinical studies with an Fc engineered IgA2m(1) antibody containing the variable regions of the EGFR antibody cetuximab. Compared with wild-type IgA2m(1), the engineered molecule lacked two N-glycosylation sites (N166 and N337), two free cysteines (C311 and C472), and contained a stabilized heavy and light chain linkage (P221R mutation). This novel molecule displayed improved production rates and biochemical properties compared with 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 because the novel IgA antibody demonstrated therapeutic activity also in non-FcαRI 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.
Highlights
The EGFR constitutes an established tumor target antigen, which can be involved in tumorigenesis [1], and which is overexpressed or mutated in many common solid tumor types such as colorectal, head and neck, and lung cancer [2]
We describe the rational design of an engineered IgA antibody directed against EGFR
In order to further investigate the immunotherapeutic activity of IgA2.0 in immune competent mice, we evaluated if the engineered IgA antibody was able to prevent tumor engraftment in a syngeneic long-term tumor model in BaF3-EGFR cells in C57BL/6 (BL6) mice (Fig. 5G)
Summary
The EGFR constitutes an established tumor target antigen, which can be involved in tumorigenesis [1], and which is overexpressed or mutated in many common solid tumor types such as colorectal, head and neck, and lung cancer [2]. Both tyrosine kinase inhibitors and monoclonal antibodies have been success-. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Lohse: Institute of Virology, Saarland University Medical Center, Homburg, Germany; and current address for S. Molecular Gastroenterology/Medical Department 1, University Hospital Schleswig-Holstein, Lu€beck, Germany.
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