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IgA as new anti-cancer therapeutic antibody

Thursday 3 February 2011

IgA as new anti-cancer therapeutic antibody
Ing. Marco Jansen and dr Jeanette Leusen


Project
Currently all anti-cancer therapeutic monoclonal antibodies in the clinic are of IgG isotype. IgG antibodies mainly exert their effect through engagement of Fcgamma receptors (FcgR), whereas IgA antibodies use FcaR. Using bispecific antibodies that engage both the tumor target and FcR, FcaR was more potent in tumor killing than FcgR. Recently, this has been confirmed using monomeric IgA antibodies: human peripheral neutrophils were able to kill IgA opsonized tumor targets in vitro more efficiently than with IgG.

The anti-tumor activity of IgA antibodies, however, has only recently been tested in vivo, due to the difficulties in IgA production and to the fact that mice do not express FcaRI. In order to explore the potency of human IgA antibodies in vivo we made use of human FcaRI transgenic mice and use both syngeneic and xenograft tumor models. In these models human IgG anti-tumor antibodies are able to prevent tumor outgrowth. In collaboration with Thomas Valerius in Germany human IgA1 and IgA2 variants of the EGFR antibody cetuximab have been generated and purified . The in vivo activity of IgG and IgA1 and IgA2 EGFR antibodies were directly compared (Boross et al, EMBO MM, 2013).




Figure 1. IgA1 and IgA2. IgA1 has a longer hinge region, but IgA2 is more effective in antibody therapy in vitro.

In this project IgA antibodies directed against CD20 for hematological cancers will be extensively characterized in vitro. Within the immunotherapy group, we generated novel CD20 antibodies for the treatment of B cell malignancies. These new antibodies need to be investigated for target binding, inhibition of signaling and proliferation and killing capacity in chromium-release ADCC (antibody-dependent cellular cytotoxicity) assays and CDC (complement dependent cytotoxicity) assays.

Techniques
Cell culture, isolation of leukocytes from human blood, in vitro killing assay (ADCC) with primary neutrophils and macrophages, growth inhibition assay, FACS, ELISA, Western blot and transfections

Duration
6 or 9 months

Contact
Dr Jeanette Leusen, jleusen@umcutrecht.nl
Dr Kristin Denzer, k.denzer@umcutrecht.nl, 088 75 643 68

References
Boross P et al, EMBO mol med 2013 Aug;5(8):1213-26
Dechant M et al. J Immunol. 2007 Sep 1;179(5):2936-43.

Dechant M et al. Blood. 2002 Dec 15;100(13):4574-80