Rare & Ultra Rare Diseases
Type II immune hypersensitivities are driven by pathological antibodies targeting self-antigens, either naturally occurring or due to exposure to an exogenous substance present on the cellular exterior or ECM. This disease type makes up many of the most prevalent autoimmune diseases, including pernicious anemia, Grave disease, and myasthenia gravis, as well as autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia. In addition, these diseases may occur after the administration of a new drug or following certain infections. Currently, therapies for these immunemediated diseases remain relatively nonspecific via broad immune suppression. For instance, comprehensive immune suppression through systemic glucocorticoids (i.e., prednisone, methylprednisolone), cytotoxic drugs (i.e., cyclophosphamide, methotrexate, azathioprine), and monoclonal antibodies (i.e., rituximab, belimumab, infliximab) dominate treatment regimens to prevent further tissue destruction.
Specifically for antibody-induced anemia, auto-antibodies attack surface antigens present on RBCs. Therapy for AIHA is relatively standardized, with patients starting on systemic steroids and escalating to cytotoxic drugs and B celldepleting monoclonal antibodies, and then possibly splenectomy based on patient response to therapy. The shortcoming of suppressing the immune system with drug-based therapies is the considerable iatrogenic risk associated with nonspecific therapy and heightened susceptibility to severe infections following spleen removal. DIA, which can be the result of drug-hapten antibodies or drug-independent autoantibodies, is treated much the same way, with discontinuance of the offending drug and, much more often than in AIHA, performance of blood transfusions. A subsequent limitation of repeated transfusions of packed RBCs is that although they revive tissue perfusion, they carry the risks of hemolytic transfusion reactions, the formation of alloantibodies, and iron toxicity. Although these approaches to therapy is effective for some patients in achieving remission, their efficacy remains variable and there is a well-established risk of adverse side effects, highlighting the need for better tailored therapies.
Nanosponges retain and present natural red blood cell membrane and surface antigens, which bare the target epitopes involved in antibody-mediated cellular clearance found in antibody-induced anemia. They have been shown to clear pathological antibodies in murine model of antibody-induced anemia. Unlike conventional immune therapy, these biomimetic nanoparticles have no drug payload to suppress normal lymphocytes or immune effector cells. Additionally, unlike blood transfusions, which serve as a replacement therapy, nanosponges deplete circulating antibody levels without contributing further toxic metabolites due to the hemolysis of transfused cells. Moreover, it has been demonstrated in animal models of autoimmune diseases that the primary target antigens can vary and shift over the course of the diseases. Exploiting target cell membranes in their entirety overcomes the varying antigen specificities and presents a previously unidentified approach in intercepting the autoreactive antibody mechanism of type II immune hypersensitivity reactions.
Schematic representation of nanosponges neutralizing hemolytic anti-RBC antibodies. (A) Anti-RBCs opsonize RBCs for extravascular hemolysis, via phagocytosis, as observed in autoimmune hemolytic anemia and drug-induced anemia. (B) Nanosponges absorb and neutralize anti-RBC antibodies, thereby protecting RBCs from phagocytosis.