A Single Dose of CD117 Antibody Drug Conjugate Enables Autologous Gene-Modified Hematopoietic Stem Cell Transplant (Gene Therapy) in Nonhuman Primates

Autologous hematopoietic stem cell transplantation (Auto-HSCT) with gene-modification techniques represents a potential cure for multiple genetic blood diseases. Despite its broad curative potential, auto-gene modified HSCT is currently limited due to morbidity/mortality from cytotoxic chemotherapy-based conditioning, including risks of secondary malignancies, organ toxicity, and infertility. To overcome these limitations, we have developed antibody drug conjugates (ADC) targeting CD117 (C-KIT) to specifically deplete the hematopoietic stem and progenitor cells (HSPC) prior to auto-gene modified HSCT. We have previously shown that the anti-CD117 ADC is highly effective at killing human CD117+ cells in vitro and in vivo (Pearse et al., Blood 2018 132:3314). To validate CD117 as an appropriate antigen for targeted ADC-mediated depletion prior to HSCT, we developed an optimized non-human primate (NHP) tool anti-CD117 ADC and evaluated it in an auto-gene modified HSCT in the rhesus macaque model. The tool CD117-ADC is potent on primary human and NHP CD34+ cells in vitro with EC50 of 0.2 and 0.09 pM respectively (Figure 1A). Humanized NSG mice treated with the tool CD117-ADC had full depletion of human HSPCs in the bone marrow 21 days after a single administration of the ADC, while maintaining the peripheral immune cells. We next tested the efficacy and safety of the tool CD117-ADC in NHPs. A single administration of the tool CD117-ADC was fully myeloablative (>99% HSPC depletion) and comparable to HSPC depletion observed following busulfan conditioning (6 mg/kg, once daily for 4 consecutive days). There was no effect on the peripheral and bone marrow lymphocytes and the ADC was well tolerated. To facilitate the use in HSCT, the tool CD117-ADC was engineered to have a fast clearance and in this study the half-life was