Bone marrow or stem cell transplantation
Hematopoietic stem cell transplant (HSCT) is a validated therapeutic approach able to achieve durable remission in patients with hematologic and autoimmune diseases. However, the side effects of current radiation and chemotherapy based conditioning regimens used to prepare patients for HSCT greatly limit the use of this powerful therapeutic approach. To circumvent these issues, we are developing antibody drug conjugates (ADCs) targeting CD45, a cell surface protein expressed throughout the hematopoietic system to enable simultaneous myelo and lympho-depletion prior to allogeneic transplant for hematological malignancies and autologous transplant for severe autoimmune diseases. Here we report that our CD45-targeted ADCs, conjugated to a non-genotoxic payload, can broadly and effectively deplete human hematopoietic cells in humanized NSG mice. This targeted depletion also confers potent anti-leukemia effects in multiple models of human hematopoietic malignancies, including patient-derived AML xenografts, where median survival times were extended greater than 2-fold. Further, we have established that single-dose administration of CD45-targeting ADCs with a non-genotoxic payload to cynomolgous monkeys achieved >80% depletion of peripheral blood lymphocytes and >85% depletion of both HSCs and lymphocytes in bone marrow at a dose that was well tolerated. The potent efficacy and tolerability of these ADCs support this novel approach for safer conditioning prior to HSCT, with the potential to dramatically increase the number of oncology and autoimmune patients that are eligible for transplant and significantly reduce the side effects associated with current conditioning protocols.