The introduction of monoclonal antibodies into clinical oncology yielded survival benefits for cancer patients by selectively targeting tumor-associated antigens (TAAs). Current research aims at making these immunotherapies even more effective. One promising approach is to use antibody classes other than IgG such as IgE. This study thus investigates the potential of specific anti-HER2 (human epidermal growth factor receptor-2) IgE antibodies in a vaccination approach comparing wildtype (wt) with transgenic hyper- or hypo-IgE mice.
Three different mice strains were employed: wt BALB/c mice, KN1 mice displaying 4- to 6- fold elevated mean serum IgE levels (1), and DM1M2 transgenic mice that lack the transmembrane and cytoplasmic domains of membrane-bound IgE resulting in reduced serum IgE levels down to 5% of wt mice (2). Each strain was divided into groups 1-4 (n=8): Groups 1. were immunized against HER-2 prior to tumor grafting, 2. against irrelevant antigen BSA, 3. passively received the anti-HER-2 IgG mouse monoclonal antibody 4D5, 4. remained naïve. Then, all mice were grafted with D2F2E2 tumor cells overexpressing HER-2 and monitored for tumor growth and survival.
When remaining naïve, all KN1 hyper-IgE mice showed significantly slower tumor growth and longer survival compared to the wt BALB/c controls and DM1M2 hypo-IgE mice. In all strains of mice passive immunotherapy with 4D5 rendered significant survival benefits compared to the untreated groups. Vaccination against HER-2 resulted in the overall longest survivals and lead to significant survival benefits compared to naïve as well as passively 4D5 antibody treated groups. Most importantly, all KN1 hyper-IgE mice showed a significant survival benefit independent of any of the treatments.
Active vaccination surmounts the effects of passive antibody therapy in the mouse model, but the presence of IgE tops the antigen-specific experiments. This study therefore suggests that IgE antibodies may play a significant role in innate cancer surveillance as well as during active anti-cancer immune responses.
(1) Migration of antibody secreting cells towards CXCL12 depends on the isotype that forms the BCR. Achatz-Straussberger G et al. European Journal of Immunology 2008;38(11):3167-77.
(2) Effect of transmembrane and cytoplasmic domains of IgE on the IgE response. Achatz G et al. Science 1997; Apr 18;276(5311):409-11.