ENGINEERING THE MODULARITY OF SINGLE DOMAIN ANTIBODY TARGETING MHC CLASS II TO PROTECT AGAINST AUTOIMMUNE DISEASES
- Novalia Pishesha, United States of America
Abstract
Background and Aims
Therapies for autoimmune diseases are traditional immunosuppressive regimens, exposing patients to higher risks of opportunistic infection and other discomforts. Here, we propose a novel strategy for antigen-specific tolerance induction that is completely proteinaceous, based on the use of adducts formed between alpaca-derived single domain antibody fragments (VHHs/nanobodies) and a diverse set of autoantigens.
Methods
We have reported that we have developed VHHs that recognize MHC-II molecules and hence, target all subsets of professional antigen presenting cells (APCs). We also established an engineering strategy that uses chemo-enzymatic approaches that enable the site-specific modifications of these VHHs at their C-terminus. These methods allow the installation of various autoantigens involved in various autoimmune diseases. We hypothesize that targeted antigen delivery to the APCs in a tolerogenic manner in the steady state and in the absence of inflammatory signal will lead to antigen-specific tolerance.
Results
We found that transfusion of a single dose of VHHMHCII-MOG35-55 completely prevents signs of disease in an experimental autoimmune encephalomyelitis. These mice are protected for the rest of their lifetime. To test the applicability of our strategy beyond a specific organ and genetic background, we expanded our tolerogenic strategy to a mouse model of type 1 diabetes; mice transfused with our VHHMHCII-p31 maintain normoglycemia in prophylactic and semi-therapeutic settings. This tolerogenic process is antigen-specific, leaving the rest of the immune system intact.
Conclusions
These results highlight the potential of these nanobody-antigen adducts to induce antigen-specific tolerance. We envision these engineered nanobodies as a novel means for treating a wide range of autoimmune diseases.