Preclinical development of 1B7/CD3, a novel anti-TSLPR bispecific antibody that targets CRLF2-rearranged Ph-like B-ALL.

Patients harboring CRLF2-rearranged B-lineage acute lymphocytic leukemia (B-ALL) face a 5-year survival rate as low as 20%. While significant gains have been made to position targeted therapies for B-ALL treatment, continued efforts are needed to develop therapeutic options with improved duration of response. Here, first we have demonstrated that patients with CRLF2-rearranged Ph-like ALL harbor elevated thymic stromal lymphopoietin receptor (TSLPR) expression, which is comparable with CD19. Then we present and evaluate the anti-tumor characteristics of 1B7/CD3, a novel CD3-redirecting bispecific antibody (BsAb) that co-targets TSLPR. In vitro, 1B7/CD3 exhibits optimal binding to both human and cynomolgus CD3 and TSLPR. Further, 1B7/CD3 was shown to induce potent T cell activation and tumor lytic activity in both cell lines and primary B-ALL patient samples. Using humanized cell- or patient-derived xenograft models, 1B7/CD3 treatment was shown to trigger dose-dependent tumor remission or growth inhibition across donors as well as induce T cell activation and expansion. Pharmacokinetic studies in murine models revealed 1B7/CD3 to exhibit a prolonged half-life. Finally, toxicology studies using cynomolgus monkeys found that the maximum tolerated dose of 1B7/CD3 was ≤1 mg/kg. Overall, our preclinical data provide the framework for the clinical evaluation of 1B7/CD3 in patients with CRLF2-rearranged B-ALL.

Spiny mice activate unique transcriptional programs after severe kidney injury regenerating organ function without fibrosis.

Fibrosis-driven solid organ failure is an enormous burden on global health. Spiny mice (Acomys) are terrestrial mammals that can regenerate severe skin wounds without scars to avoid predation. Whether spiny mice also regenerate internal organ injuries is unknown. Here, we show that despite equivalent acute obstructive or ischemic kidney injury, spiny mice fully regenerate nephron structure and organ function without fibrosis, whereas C57Bl/6 or CD1 mice progress to complete organ failure with extensive renal fibrosis. Two mechanisms for vertebrate regeneration have been proposed that emphasize either extrinsic (pro-regenerative macrophages) or intrinsic (surviving cells of the organ itself) controls. Comparative transcriptome analysis revealed that the Acomys genome appears poised at the time of injury to initiate regeneration by surviving kidney cells, whereas macrophage accumulation was not detected until about day 7. Thus, we provide evidence for rapid activation of a gene expression signature for regenerative wound healing in the spiny mouse kidney.

Smoking status identification: two managed care organizations' experiences with a pilot project to implement identification systems in independent practice associations.

OBJECTIVE: To determine whether managed care organizations (MCOs) can effectively promote the sustained use of smoking status identification systems among independent practice associations. STUDY DESIGN: Quasi-experimental design measuring smoking status documentation before and after an intervention. METHODS: A chart review of the MCOs' patients at 4 participating primary care clinics determined the baseline for smoking status documentation before intervention. Baseline data were unavailable from a fifth participating clinic. Two quality improvement personnel were sent by the MCOs to help the clinics chose and implement a system for identifying smoking status. All of the clinics chose a sticker system. The change in smoking status documentation was assessed by chart reviews of patients enrolled in the MCOs who were seen during the period between 3 and 16 months after implementation of the system. RESULTS: Following the intervention, a significant increase in smoking status documentation was noted among participating clinics. The proportion of patients whose smoking status was identified and documented by any method increased from 50% to 87% (P < .01) at the 4 clinics with baseline data. By clinic, the increase varied from 6% to 60%. The sticker system was the method by which most patients' smoking status was documented (77%). There were no controls, so the influence of outside factors, including a regional smoking cessation campaign that coincided with this study, cannot be quantified. CONCLUSIONS: Managed care organizations may be an effective change agent for implementing the guidelines for tobacco use and dependence treatment.