Successful engraftment of hematopoietic stem cells (HSCs) involves overcoming nonimmunologic barriers that hinder access to the HSC niches in the bone marrow (BM). 1, 2 Cytotoxic chemotherapy and/or radiation are currently used to reduce these barriers in clinical hematopoietic cell transplantation (HCT). 1, 2 Targeted and safer methods to eliminate endogenous HSCs to achieve niche clearance would substantially reduce the morbidity and mortality of an HCT. 3 We previously showed that an anti-mouse monoclonal antibody targeting CD117, a cytokine receptor tyrosine kinase expressed on HSCs, depletes endogenous HSCs and allows donor HSC engraftment in immunodeficient mice. 4-6 Signals transmitted through CD117 after interaction with its ligand, stem cell factor, are critical for HSC survival, proliferation, and differentiation. 4, 7

We identified a humanized anti-human CD117 immunoglobulin G1 monoclonal antibody, AMG 191, as a candidate therapeutic antibody with the potential to achieve BM HSC niche clearance for use as conditioning for clinical HCT. Prior studies showed that AMG1 191 and its parent clone, SR-1, from which AMG 191 was derived block stem cell factor binding to CD117 thereby interrupting the signals transmitted through this receptor. 8, 9 We assessed AMG 191 for its ability to safely target and deplete hematopoietic stem and progenitor cells (HSPCs) in the BM of nonhuman primates (NHPs) and human HSPCs xenografted into immune-deficient mice. We first confirmed that AMG 191 binds to human and NHP HSCs by immunophenotypic analysis and that AMG 191 impairs hematopoiesis of human and NHP HSCs in in vitro studies (supplemental Figure 1, available on the Blood Web site). The HSPC-depletive in vivo activity of AMG 191 was then tested in NHPs (Figure 1). Immunocompetent juvenile cynomolgus macaques received a single IV infusion of AMG 191 (0.1, 1, 5, or 25 mg/kg). All animals survived to the end of study and there were no adverse clinical observations attributable to treatment with AMG 191 (data not shown). The pharmacokinetic (PK) clearance of AMG 191 in the serum was dose dependent in a nonlinear fashion (Figure 1A). Phenotypic CD341 HSPCs were depleted in the BM of all animals that received AMG 191 except NHP# 7 (Figure 1B-C). Of note, at the time of infusion, NHP# 7 had emesis, markedly elevated neutrophils, and white blood cells, suggesting that it was ill (supplemental Figure 2), which may have influenced this animal’s physiologic state. HSPC depletion lasted up to 21 days in most animals and. 42 days in