IFNg SMC: A New Approach to Mesenchymal Stem Cell Therapy

Cellular therapies have demonstrated great promise and exceptional safety profiles in clinical trials. However, except for a subset of autologous therapies, manufactured at small scale, regulatory approval and wide commercial success has been lacking for allogeneic products for treatment of large patient populations. Issues impeding success include high costs of production, low scalability, low or variable control of manufacturing parameters, causing lot-to-lot variation, and complex cold-chain logistics. Ossium Health is developing an allogeneic mesenchymal stem cell (MSC) therapy for treatment of inflammatory diseases, beginning with acute GVHD. The source of MSC is bone marrow (BM) from deceased organ donors that has been recovered and processed in accord with Good Manufacturing Practice (GMP). This unique source of BM provides for an abundant supply of primary MSCs, with yields >2000-fold over what was previously obtainable from limited volumes aspirated from living donors. Processes have been optimized to overcome each of the issues described above. Key innovations are presented.Through partnerships with over 50% of US Organ Procurement Organizations (OPOs), Ossium has exclusive access to an abundant supply of deceased donor BM. Hundreds of donors are prescreened for optimal characteristics for manufacturing and clinical end use. Engineering of the expansion medium and scheme have allowed for manufacturing hundreds of trillions of low passage MSC from a single donor via a tiered banking system (Figure 1). Safety is further ensured by rigorous testing at each hold stage in the process. The expansion process is capped by further enhancing potency through priming with interferon gamma (IFNg) to stimulate immunomodulatory function. Moreover, issues with poor post-thaw function have been addressed by including a synchronization step which uniformly preserves cells in a state which protects them from cryopreservation injury. Given the unique processes employed to enhance and preserve function, we have termed these MSCs IFNg-primed synchronized mesenchymal stem cells (gSMC) to differentiate them from non-similarly enhanced MSCs. Consistency between batches and lots is ensured by employing a matrix of potency-indicating assays. At the end of production, gSMC are suspended in a cryopreservation medium with a low (5%) dimethyl sulfoxide (DMSO) concentration and cryopreserved by a gentle passive cooling process before storing in the vapor phase of liquid nitrogen (LN2). Doses of gSMC are shipped to clinical sites using validated LN2 dry shippers and end-users are supplied with a dry thawing device and trained on its use to ensure appropriate thawing prior to injection. This highly engineered manufacturing scheme overcomes many of the previous barriers to MSC therapeutic development by ensuring consistency, which has been missing in previous MSC therapy development programs.