Project Details
Projekt
Effector mechanisms of IgA antibodies against CD20
Subject Area
Hematology, Oncology
Term
from 2015 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 278247522
The CD20 antibody rituximab has significantly contributed to the improved survival of patients with different types of B cell lymphomas. Additional progress is expected in the near future from the approval of novel antibodies. With respect to their mechanisms of action, CD20 antibodies can be grouped into two different types: type I antibodies are efficient in mediating complement dependent cytotoxicity (CDC), while type II antibodies are particularly efficient in triggering tumor cell apoptosis. As human IgG1 antibodies, both types of molecules are able to recruit NK cells and monocytes/macrophages for antibody-dependent cellular cytotoxicity (ADCC). Our own previous work has demonstrated that human IgG1 antibodies - particularly when they were engineered to achieve higher affinity for FcgammaRIII (CD16) - do not rigger ADCC by granulocytes. However, granulocytes are particularly well activated by antibodies of human IgA isotypes. Natural IgA antibodies constitute an integral part of the mucosal immune system, but their role as therapeutic reagents in tumor immunotherapy has not been adequately addressed. Recently, we established production and purification technologies to generate sufficient amounts of recombinant human IgA antibodies. Within the proposed project variable regions of select type I (rituximab and ofatumumab) and type II (obinutuzumab) CD20 antibodies shall be produced as IgA1 and IgA2 molecules. These antibodies shall then be functionally compared to their respective IgG1 molecules in vitro and in vivo. Results of these experiments shall improve our understanding of the relevant mechanisms of action of CD20 antibodies and support the development of improved reagents. Additionally, we expect novel insights into the immunotherapeutic potential of IgA antibodies.
DFG Programme
Research Grants
International Connection
Netherlands, United Kingdom
Cooperation Partners
Professor Dr. Mark Cragg; Professor Dr. Martin Glennie; Professorin Dr. Jeanette Leusen
