Deimmunization and Immune Tolerance Strategies for Protein Therapeutics: Extension of Principles to Novel Therapeutic Modalities.

For protein therapeutics, the need for repetitive courses of agents that often invoke immune responses such as mAbs for treatment of autoimmune/immunoinflammatory disorders and enzyme/coagulation factor replacement therapies for lysosomal storage diseases and coagulopathies has required novel approaches of deimmunization, therapeutic drug monitoring (for some agents) and immune tolerance induction. new methods that enhance the accuracy of prediction algorithms for such therapeutics such as MAPPs-based assays and in vitro immunogenicity assays improve the predictions and accuracy of epitope targets in therapeutic proteins.

Novel therapeutics such as AAV gene therapies may invoke the need for retreatment as transduced cells die and are replaced by cells lacking the transgene and the therapy wanes. Although similar approaches to preventing or mitigating immunogenicity of therapeutic proteins may be considered, the risks differ. For gene therapy, deimmunization or development of novel AAV capsids lacking sequence similarity to the first treatment is preferable to tolerance induction as tolerance to capsid may inadvertently render the recipient more susceptible to AAV or other viruses with cross conserved capsid determinants. For CAR-T cellular immunotherapy of cancer, in which immune responses to retained murine or foreign elements of the CAR receptor diminish or eliminate a potent anti-tumor response. tolerance induction to CAR-T may inadvertently abrogate a critical anti-tumor immune response. Thus, for CAR-T cell therapy and other modalities in which the therapeutic is generated inside the host cells, consideration must be given to further deimmunization strategies including use of immunoinformatic approaches and associated MAPPS and in vitro assays to identify CTL epitopes in addition to T helper epitopes. Novel cellular approaches for treatment of LSDs/Coagulopathies or for transplantation tolerance are highly promising: gene modified HSC or allogeneic HSC are administered following ablation of host HSC via CD117-Saporin immunotoxin administration leading to robust engraftment of gene modified/allogeneic donor cells and allowing for long term, perhaps curative treatments without the need for retreatment unless initial engraftment is inadequate