Immune tolerance to recombinant immunotoxin LMB-100 using synthetic vaccine particles encapsulating rapamycin

Abstract

Abstract Protein and cell based therapeutics have great potential to treat many human diseases. However, they often elicit an immune response that blocks their efficacy. Synthetic Vaccine Particles containing Rapamycin (SVP-R) is a novel approach to mitigate immunogenicity and induce specific immune tolerance. We evaluated the efficacy of SVP-R to reduce anti-drug antibody (ADA) formation to a recombinant immunotoxin, LMB-100, a genetically engineered protein designed for cancer therapy. Due to the bacterial origin of the toxin, LMB-100 is highly foreign to the human immune system. Almost all patients treated with LMB-100 made ADAs after two cycles (6 doses) of treatment that neutralized the drug and greatly lowered efficacy. Using an immune-competent mouse model we found that combining SVP-R with LMB-100 dramatically decreased ADA titers by 98%. The decrease persisted for more than six weeks despite additional challenges with LMB-100, indicating development of immunological tolerance to LMB-100. Transfer of splenocytes from tolerized mice to naïve mice, and challenge with LMB-100 resulted in a 66% decrease in titer, indicating that the immune tolerance is transferable. SVP-R are being evaluated in humans to prevent ADA to Pegsiticase, an enzyme for refractory gout treatment. Our data indicates that combining SVP-R with LMB-100 should be useful in treating cancer by allowing more treatment cycles and better efficacy. This approach can be used to increase the efficacy of other immunogenic agents such as CAR-T cells, antibody drug conjugates and viral gene therapy vectors.