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  An Anti-EGFR IgA That Displays Improved Pharmacokinetics and Myeloid Effector Cell Engagement In Vivo

Lohse, S., Meyer, S., Meulenbroek, L. A., Jansen, J. M., Nederend, M., Kretschmer, A., et al. (2016). An Anti-EGFR IgA That Displays Improved Pharmacokinetics and Myeloid Effector Cell Engagement In Vivo. Cancer Research, 76(2), 403-417. doi:10.1158/0008-5472.CAN-15-1232.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0029-7529-1 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0029-752A-0
Genre: Journal Article

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 Creators:
Lohse, Stefan, Author
Meyer, Saskia, Author
Meulenbroek, Laura A.P.M., Author
Jansen, J.H. Marco, Author
Nederend, Maaike, Author
Kretschmer, Anna, Author
Klausz, Katja, Author
Möginger, Uwe1, Author              
Derer, Stefanie, Author
Rösner, Thies, Author
Kellner, Christian, Author
Schewe, Denis, Author
Sondermann, Peter, Author
Tiwari, Sanjay, Author
Kolarich, Daniel1, Author              
Peipp, Matthias, Author
Leusen, Jeanette H.W., Author
Valerius, Thomas, Author
Affiliations:
1Daniel Kolarich, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society, ou_1863301              

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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. Cancer Res; 76(2); 403–17. ©2015 AACR.

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 Dates: 2016-01-15
 Publication Status: Published in print
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Title: Cancer Research
Source Genre: Journal
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Publ. Info: Baltimore, Md. : Waverly Press
Pages: - Volume / Issue: 76 (2) Sequence Number: - Start / End Page: 403 - 417 Identifier: ISSN: 0008-5472