Nanoparticle-mediated restoration of pomalidomide sensitivity in multiple myeloma

Multiple myeloma (MM), a plasma cell malignancy, is the second most common hematologic malignancy in the United States after non-Hodgkin lymphoma. Treatment options include immunomodulatory imide drugs (IMiDs). FDA approved IMiDs (thalidomide, lenalidomide, and pomalidomide) have remained among the primary treatments for MM and have helped extend the lifespan of patients up to several years after diagnosis. IMiDs bind to cereblon (CRBN), a component of E3 ubiquitin ligase, to exert their anti-proliferative effect on myeloma cells. While the majority of newly diagnosed myeloma patients respond to treatment with IMiDs, most eventually develop resistance. Cereblon genetic alterations contribute about one-third of acquired resistance observed in the clinic. We aim to restore sensitivity to pomalidomide-resistant cells through nanoparticle-mediated delivery of wildtype cereblon mRNA to cells. We designed lipid nanoparticles and used it to deliver in vitro transcribed cereblon mRNA to pomalidomide-resistant MM1.S cells. We showed that the lipid nanoparticle efficiently delivered cereblon mRNA to the resistant cells with subsequent restoration of pomalidomide sensitivity. Next, delivery of cereblon mRNA-loaded nanoparticles precisely to malignant plasma cells is important to ensure the desired outcome. Among cell surface proteins, B-cell maturation antigen (BCMA) and CD38 are known to be highly expressed by multiple myeloma cells. We therefore screened for peptides that bind to BCMA and CD38 using phage display libraries. Following DNA sequencing, three clones containing cyclic peptides with affinity for these proteins were identified. These peptides have been synthesized and are being tested; they will be conjugated with the nanoparticle-coated cereblon mRNA for targeted delivery to the malignant plasma cells. Our results show that delivery of cereblon mRNA to pomalidomide-resistant cells using lipid nanoparticles led to substantial restoration of pomalidomide sensitivity.