Jul 9: Monoclonal IgA antibody therapy: Instigating neutrophils against cancer
Using IgA (rather than IgG) antibody therapy, it was possible to attack tumor cells in lymphoma and neuroblastoma, leading to efficacy in preclinical models and a reduction in side effects. In addition, IgA antibodies could positively influence the tumor microenvironment, with which immunotherapeutic treatments could possibly be improved. These were the main findings in the PhD thesis by Mitchell Evers who obtained his doctorate title from Utrecht University on July 9.
Monoclonal antibody therapy is currently used to treat various types of cancer. Although this strategy has improved treatment, there is still a lot of recurrence and mortality is still high. All of these therapies are of the IgG type. Although the use of monoclonal antibodies of the IgG1 isotype has had a major impact on patient survival for several cancer types, cure is often not achieved.
Activating neutrophils
In his thesis Mitchell Evers (Center for Translational Immunology, UMC Utrecht) and colleagues investigated monoclonal antibodies of the IgA type against cancer. The unique property of this type of antibodies (and in contrast to IgG) is that they strongly activate the neutrophil, the most abundant immune cell in the human body. With this strategy, they were able to attack these cells in lymphoma and neuroblastoma, leading to efficacy in preclinical models and a reduction in side effects. In addition, IgA antibodies could positively influence the tumor microenvironment, with which immunotherapeutic treatments could possibly be improved.
Valuable mechanism of action
Mitchell Evers concludes: “We show that monoclonal antibodies of the IgA isotype provide valuable mechanisms of action not demonstrated by other antibody isotypes. IgA antibodies efficiently trigger activation of the Fcα receptor, expressed on neutrophils and macrophages, thereby recruiting these cells against cancer. Additionally, we show that IgA antibodies can be of benefit for indications where complement activation is undesired, such as for GD2-based therapy of neuroblastoma. Moreover, we have shown that IgA can benefit from a tumor microenvironment containing polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCSs). We were able to specifically activate both PMN and PMN-MDSCs against cancer after IgA treatment, thereby indirectly improving T cell proliferation.”
Increasing knowledge
Nevertheless, Evers believes that the step towards clinical application of IgA still has to be undertaken. With the large number of novel antibody targets emerging each year, it is important to further increase the available knowledge on antibody therapy to allow selecting the best antibody format for each antigen. He believes that this can be achieved by using the complete array of the available antibody formats, which can eventually improve the overall success of immunotherapy.
PhD defense
Mitchell Evers (1991, Breda) defended his PhD thesis on July 9, 2020 at Utrecht University. The title of his thesis was “Monoclonal IgA antibody therapy: Instigating neutrophils against cancer”. Supervisor was prof. dr. Erik Hack and Co-supervisor was dr. Jeanette Leusen (both Center for Translational Immunology, UMC Utrecht).