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Successful hematopoietic cell transplantation (HCT) requires vacating recipient hematopoietic stem cell (HSC) niches to permit donor HSC engraftment to provide life-long hematopoietic and immune function. Currently HCT relies on DNA damaging radiation or chemotherapy to achieve HSC niche clearance. We have pursued a non-toxic approach to target and deplete HSC using humanized monoclonal antibody, AMG 191, that binds human CD117 (c-Kit). We opened a Phase 1 dose escalation trial using AMG 191 as the sole conditioning agent to achieve donor HSC engraftment in patients undergoing HCT for severe combined immunodeficiency (SCID). The primary endpoint is to assess the safety of administering AMG 191. Secondary endpoints include AMG 191 pharmacokinetics (PK), host HSC depletion, and determination of the dose of AMG 191 that achieves adequate donor HSC engraftment, defined as >5% donor granulocyte chimerism at 24 weeks. We have completed the first dose cohort of patients receiving 0.1 mg/kg AMG 191 and treated the first two patients in the second cohort (0.3 mg/kg). All five patients tolerated the AMG 191 infusion and the subsequent infusion of their CD34-selectd donor cells without clinical problems. Here we report efficacy in the first two patients, who have reached the 24-week timepoint. Both patients had T-B-NK+ SCID with mutations in the DCLRE1C (Artemis) gene. Both previously received unconditioned HCT as infants, failed to develop donor B cells and remained dependent on exogenous immunoglobulin. CD34-selected mobilized peripheral blood cells from the original donors were infused when the AMG 191 serum level was Conclusion: These data are proof of concept that a humanized monoclonal antibody targeting CD117 can safely clear human HSC niches and facilitate donor HSC engraftment. This study is ongoing and open for enrollment.

The identification of the common lymphoid progenitors in mouse bone marrow allows us to directly assess the regulatory mechanisms of lymphoid lineage commitment. The unexpected finding of a latent myeloid differentiation potential in lymphoid progenitors sheds light on the importance of cytokine receptor expression at this stage. We will discuss the biological nature of common lymphoid progenitors as a model of differentiation from multipotent to lineage committed progenitors. Elucidation of this hidden differentiation potential in progenitors will help further our understanding of the molecular mechanisms that control the cell fate determination of not only common lymphoid progenitors, but also their ancestors, hematopoietic stem cells, and their descendents such as committed T and B cell progenitors.

Murine peritoneal exudate cells (PEC), predominantly macrophages, were insonated in vitro with burst-mode ultrasound and assayed for their ability to phagocytose and kill Staphylococcus aureus . PEC were exposed at 37°C in rotating tubes to 1-MHz, burst-mode (10 ms on, 10 ms off) ultrasound at 3.7 ± 0.2 W/cm 2 I SPTA (7.4 ± 0.4 W/cm 2 I SPBA ) for 150 s. Bactericidal activity was assayed at 1, 2, and 3 h after exposure and subsequent 37°C incubation with the bacteria for 20 min. In these experiments, which comprised 17 treated and 7 sham-treated control samples, there was no significant difference in results between treated and control samples ( p > 0.29).