Oral tolerance to prevent anti-drug antibody formation in protein replacement therapies

Abstract

Protein based therapeutics have successfully improved the quality of life for patients of monogenic disorders like hemophilia, Pompe and Fabry disease. However, a significant proportion of patients develop immune responses towards intravenously infused therapeutic protein, which can complicate or neutralize treatment and compromise patient safety. Strategies aimed at circumventing immune responses following therapeutic protein infusion can greatly improve therapeutic efficacy. In recent years, antigen-based oral tolerance induction has shown promising results in the prevention and treatment of autoimmune diseases, food allergies and can prevent anti-drug antibody formation to protein replacement therapies. Oral tolerance exploits regulatory mechanisms that are initiated in the gut associated lymphoid tissue (GALT) to promote active suppression of orally ingested antigen. In this review, we outline general perceptions and current knowledge about the mechanisms of oral tolerance, including tissue specific sites of tolerance induction and the cells involved, with emphasis on antigen presenting cells and regulatory T cells. We define several factors, such as cytokines and metabolites that impact the stability and expansion potential of these immune modulatory cells. We highlight preclinical studies that have been performed to induce oral tolerance to therapeutic proteins or enzymes for single gene disorders, such as hemophilia or Pompe disease. These studies mainly utilize a transgenic plant-based system for oral delivery of antigen in conjugation with fusion protein technology that favors the prevention of antigen degradation in the stomach while enhancing uptake in the small intestine by antigen presenting cells and regulatory T cell induction, thereby promoting antigen specific systemic tolerance.

Keywords: Anti-drug antibody; Enzyme replacement therapy; FIX; FVIII; Hemophilia; IL-10; LAP; Oral tolerance; Pompe disease; Tregs.

Fig. 1:. Mechanism of oral tolerance induction to protein replacement therapy

Mechanism of oral tolerance induction: 1) Oral administration of therapeutic proteins (FVIII, FIX or GAA) expressed in the chloroplast of lettuce plant leaves. 2) Prevention of therapeutic protein degradation in the stomach from the harsh acidic environment and digestive enzymes. 3) Uptake of therapeutic protein in the intestinal lumen directly by CD103⁺ DC or indirectly through absorption by M cells and transport to Peyer’s patches or lamina propria. Antigen presenting DCs prime naïve antigen specific cells leading to iTreg generation. 4) Migration of antigen presenting DCs to MLNs and induction of different subtypes of immunosuppressive CD4⁺ T cells including iTregs, LAP Tregs and Tr1 cells, along with CCR9 expressing gut migratory Tregs. 5) Migration of immunosuppressive T cell subtypes to the periphery to develop systemic tolerance.