IgA antibodies for tumor therapy - functional evaluation of polymeric isoforms

• Applicant: Dr. Stefan Lohse
• Subject Area: Hematology, Oncology ; Immunology ; Virology
• Term: from 2012 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 213781821

Antibodies of IgA isotype are important immunoglobulins in mammalian species. While polymeric IgA antibodies neutralize pathogens across mucosal epithelia, monomeric variants defend those which passed mucosal barriers. Thereby the Fc receptor dependent engagement of myeloid cells seems to be of major importance. Since myeloid effector cells are key players in the carcinogenesis and immunotherapy of malignant diseases the evaluation of the immunotherapeutic potential of IgA antibody myeloid cell-mediated engagement for specific tumor cell killing (ADCC) seems to be a rational approach. During the previous funding period we could show that EGFR-directed dimeric IgA antibodies are significantly more effective than their monomeric counterparts in Fab- as well as in Fc-mediated effect mechanisms. However, respective animal models demonstrated that the pharmacokinetic properties and thus the in vivo efficacy of IgA antibodies are strongly influenced by their glycosylation. Based on these findings we developed strategies to optimize the glycosylation and finally designed a molecule with improved pharmacokinetic properties. Thus, one major topic of the new funding period is therefore the evaluation of the functional and pharmacokinetic properties of optimized dimeric IgA antibodies. Furthermore, the influence of the tumor micro milieu and EGFR- and ADCC-modulating proteins on myeloid cell polarization and the IgA-dependent engagement of myeloid cells for the specific lysation of tumor cells will be investigated. From these experiments we expect in deep knowledge of functional properties of IgA antibodies and of the FcalphaRI-dependent activation of myeloid cells as a promising alternative approach for the development of potential immunotherapeutic strategies.

• DFG Programme: Research Grants
• International Connection: Netherlands
• Cooperation Partner: Professorin Dr. Jeanette Leusen