Development of a universal approach to block inhibitors for protein replacement therapy

About This Grant

NabGen is developing an engineered and long half-life Protein M, a mycoplasma-derived protein, for blocking alloantibodies (inhibitors) for clinical applications and thus enabling the improved outcome of biological drug treatment in patients with antidrug antibodies (ADA), such as inhibitors from protein replacement treatment (PRT) in lysosomal storage diseases and hemophilia. The development of inhibitors to the infused proteins is the major complication in PRT. The costs of treatment for patients with inhibitors are 5-fold higher than patients without inhibitors. Additionally, patients with inhibitors suffer more severe diseases and hospitalization. Although many approaches have been used in clinical practice including deletion of B cells or T cells, high- dose of IVIG, induction of immune tolerance, these approaches often take long-time management and don’t work for each patient. Recently, we have demonstrated that Protein M binds to all immunoglobulin from any mammalian species with high affinity and is able to block immunoglobulin function. Our preliminary data shows that Protein M can reduce neutralizing antibody (Nab) activity by 100-fold in vitro and 1000-fold in animals when paired with a gene delivery vector, adeno-associated virus (AAV). Development of the Protein M-based strategy has significant advantages for blocking inhibitor/alloantibody activity, as Protein M: 1) has universal function, 2) has no effect on the biologics’ potency, 3) possesses high efficiency (100–1,000-fold prevention of inhibitors), 4) is capable of repeated administration, 5) with no severe side effects or complications seen in both small and large animals, and 6) potential low cost. Thus, to our knowledge, Protein M is the most effective approach to block inhibitors among all strategies studied so far. The wild-type protein M is not stable at room temperature. We have engineered one protein M mutant MG29 with increased thermo-stability and demonstrated that MG29 had a similar activity as wt protein M to block FVIII inhibitor activity in vitro and in vivo, in hemophilia A mice. To increase MG29 half-life, we have developed a fusion protein (MG64) with MG29 linked to an Fc domain and found the similar ability to block AAV Nabs when compared to MG29. This Phase I project seeks to explore the efficacy of fusion Protein M MG64 to protect FVIII treatment in hemophilia A mice with inhibitors. If successful, ultimately, this technology will extend the benefits to a greater population of patients with inhibitors and needing repeated administration of any biological therapy.