Endothelial Activation by Interferon Blocking Antibodies

Neutralizing antibodies to type I interferons are of therapeutic significance in a dual way: The natural occurrence of potentially inflicting, neutralizing antibodies was reported for IFN-alpha or -beta treatment of viral infections and cancer. In contrast, the clinical benefit of recombinant IFN-alpha blocking antibodies is currently evaluated for autoimmune diseases with pathogenic IFN-alpha production such as systemic lupus erythematosus. Therefore, it seems of interest to us that neutralizing antibodies previously reported to counteract IFN-alpha or - beta activity in fibroblasts or leukocytes were found to trigger an "IFN-like" response in quiescent primary human endothelial cells. Furthermore, in our initial experiments these antibodies were shown to enhance rather than inhibit type I interferon signals, whereas neutralizing antibodies to type II interferon efficiently blocked IFN-gamma activity. The stimulatory capacity of anti-IFN-alpha/beta antibodies was mediated by the constitutive autologous production of sub-threshold levels of type I interferon and involved IFN and Fc receptors. Based on our preliminary results we would like to propose a more detailed analysis of the functional impact and the underlying mechanism of the observed "IFN-like" response to IFN-neutralizing antibodies. Unraveling the mode of action will hopefully allow us to deduct whether a similar effect could be expected for other cytokines/receptors and the prospective application of blocking antibodies. With respect to type I interferons, our preliminary results would suggest that enhanced neutralizing efficiency might be achievable by applying Fab fragments versus full- length immunoglobulins in systemic therapy, which - if further substantiated in the course of this research project - would be of considerable relevance to the clinical trial currently conducted with anti-IFN-alpha neutralizing antibody in autoimmune patients.

Neutralizing antibodies to type I interferons are of therapeutic significance in a dual way: The natural occurrence of potentially inflicting, neutralizing antibodies was reported for IFN-alpha or -beta treatment of viral infections and cancer. In contrast, the clinical benefit of recombinant IFN-alpha blocking antibodies is currently evaluated for autoimmune diseases with pathogenic IFN-alpha production such as systemic lupus erythematosus. Therefore, it seems of interest to us that neutralizing antibodies previously reported to counteract IFN-alpha or -beta activity in fibroblasts or leukocytes were found to trigger an "IFN-like" response in quiescent primary human endothelial cells. Furthermore, in our initial experiments these antibodies were shown to enhance rather than inhibit type I interferon signals, whereas neutralizing antibodies to type II interferon efficiently blocked IFN-gamma activity. The stimulatory capacity of anti-IFN-alpha/beta antibodies was mediated by the constitutive autologous production of sub-threshold levels of type I interferon and involved IFN and Fc receptors. Based on our preliminary results we would like to propose a more detailed analysis of the functional impact and the underlying mechanism of the observed "IFN-like" response to IFN-neutralizing antibodies. Unraveling the mode of action will hopefully allow us to deduct whether a similar effect could be expected for other cytokines/receptors and the prospective application of blocking antibodies. With respect to type I interferons, our preliminary results would suggest that enhanced neutralizing efficiency might be achievable by applying Fab fragments versus full- length immunoglobulins in systemic therapy, which - if further substantiated in the course of this research project - would be of considerable relevance to the clinical trial currently conducted with anti-IFN-alpha neutralizing antibody in autoimmune patients.