JSP191 As a Single-Agent Conditioning Regimen Results in Successful Engraftment, Donor Myeloid Chimerism, and Production of Donor Derived Naïve Lymphocytes in Patients with Severe Combined Immunodeficiency (SCID)

Successful hematopoietic cell transplantation (HCT) relies on conditioning of recipients to deplete hematopoietic stem cells (HSC) from marrow niches to allow healthy HSC to engraft. Currently, only genotoxic chemotherapy and/or radiation are used to achieve such niche clearance. We have developed a targeted non-genotoxic approach to deplete HSC using a monoclonal antibody, JSP191, that binds human CD117 (c-Kit), a receptor tyrosine kinase expressed on HSC and progenitor cells (HSPC). We have opened a phase 1 dose escalation trial using JSP191 as the sole conditioning agent in patients with SCID (ClinicalTrials.gov: NCT02963064). HCT is the only definitive cure for SCID, a uniformly lethal genetic immune disorder. Because infants with SCID lack functional T cells which can mediate transplant rejection and because of toxicity concerns, SCID infants may receive HCT without conditioning. This approach is associated with presumed engraftment of donor lymphoid progenitors but not HSC, resulting in incomplete and poorly sustained immune reconstitution, evidenced by naïve T cell production that wane over time and absent functional B cells requiring life-long immunoglobulin (Ig) replacement. Second donor HSC transplants (“boosts”) without conditioning have not led to HSC engraftment and thus immune defects persist.