Invention from the Friedrich-Alexander-Universität Erlangen-Nürnberg for Pharmaceutics & Medicine:
Dendritic cells (DC) are considered to be the organizers of the immune system. In principle they can induce two reactions. On the one hand, they organize the immune defense for the control and elimination of microbes and foreign structures/cells, such as cancer cells. On the other hand, DCs prevent this very immune-defence from attacking endogenous cells and structures. The latter is also referred to as induction or maintenance of tolerance or briefly tolerization. When tolerance is broken, the results are graft rejections, allergies or autoimmune diseases with progressive tissue destruction as seen for example in rheumatoid arthritis and multiple sclerosis. Unfortunately, hardly any therapies or therapy regimens have been developed to date to induce tolerance. In the presented new invention it is demonstrated that the i.v. application of Ontak results in a profound tolerization of dendritic cells (DC).
A therapeutic intervention would have to modulate DC function at the time and localization of antigen presentation. In the field of allergology, a method of desensitization, for example to pollen antigens, has been developed. This method, however, does not work with all antigens and has been approved only for a few antigens with varying degree of success. In transplantation medicine, no method has been developed for „habituating“ the recipient‘s immune system to the new organ or for inducing tolerance. Therefore, graft recipients must be treated with immune suppressants for life.
Denileukin Difitox (DAB 389 IL-2; Ontak) is a drug approved in the U.S.A. and developed for elimination of CD25R bearing T cells in particular of T-cell lymphomas (CTCL) and regulatory T cells. It is supplied by the Japanese pharmaceutical company Eisai or Cephalon. It is a recombinant fusion protein produced in E. coli and consisting of fragments A and B of diphtheria toxin and human interleukin 2 (IL-2).
In the presented new invention it is demonstrated that the i.v. application of Ontak results in a profound tolerization of dendritic cells (DC). The underlying molecular mechanism was elucidated in detail, showing the upregulation of tolerogenic genes in human DC, PBMC and tissue. The tolerazing effect is demonstrated by in vitro and in vivo results including clinical data, state of the art immunological analyses, mRNA array analyses, MELC tissue technology, confocal imaging and numerous in vitro assays (Nature Medicine, submitted). We conclude that the novel effect could be used to induce antigen-specific tolerization through an easy and safe clinical procedure, for example, in transplantation medicine to avoid graft rejections, or for desensitization by means of a DC vaccine. Aside from these results, the conducted study provided novel and crucial insights into the molecular mechanism of Ontak in the treatment of CTCL and autoimmune diseases.
Bacterial Toxin/IL-2 fusion proteins (i.e. Denileukin Difitox (DAB 389 IL-2; Ontak)) can be used for
- antigen-specific tolerization, for example to avoid graft rejection
- allergy desensitization, for example severe and life threatening Latex allergy
- induce regulatory T cells in autoimmune diseases
In vivo data are available.