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.

Cascading effects of BPT for child internalizing problems and caregiver depression.

Behavioral Parent Training (BPT) is the standard of care for early onset (3 to 8years old) disruptive behavior disorders (DBDs). Preliminary evidence suggests that BPT may also produce cascading treatment effects for comorbid and interrelated symptomatology in children, primarily internalizing problems, as well as symptomatology in multiple systems of the family, including caregiver depressive symptomatology. What is less well understood, however, is why and how BPT functions to impact these multiple symptom clusters within and between family members. Accordingly, this manuscript aims to serve as a conceptual and theoretical consideration of the mechanisms through which BPT may produce generalized treatment effects among children with early onset DBDs and internalizing problems, as well as the psychosocial difficulties among their caregivers. It is our intention that the hypothesized mechanisms highlighted in this review may guide advances in clinical research, as well as assessment and practice.