Defining the Pharmacodynamic Profile and Therapeutic Index of NHS-IL12 Immunocytokine in @entity235 with XXXX .

@entity1 @entity137 @entity882 @entity1333 @entity5 @entity235 @entity14121 @entity320
BACKGROUND: Interleukin (IL)-12 is a pro-inflammatory cytokine that mediates T-helper type 1 responses and cytotoxic T-cell activation, contributing to its utility as anti- @entity5 agent. Systemic administration of IL-12 often results in unacceptable @entity137 ; therefore, strategies to direct delivery of IL-12 to @entity5 are under investigation. The objective of this study was to assist the preclinical development of NHS-IL12, an immunocytokine consisting of an antibody, which targets @entity5 regions, linked to IL-12. Specifically this study sought to evaluate the safety, serum pharmacokinetics, anti- @entity5 activity, and immune modulation of NHS-IL12 in @entity235 with naturally occurring @entity5 . METHODOLOGY/PRINCIPAL FINDINGS: A rapid dose-escalation study of NHS-IL12 administered subcutaneously to @entity235 with @entity320 was conducted through the Comparative Oncology Trials Consortium (COTC). Eleven @entity235 were enrolled in four dose-escalation cohorts; thereafter, an additional seven @entity235 were treated at the defined tolerable dose of 0.8 mg/m2. The expanded cohort at this fixed dose (ten @entity235 in total) was accrued for further pharmacokinetics and pharmacodynamics assessment. NHS-IL12 levels, serum cytokine concentrations, and peripheral blood mononuclear cell characterization (post-treatment) and draining lymph node immune profiling, and @entity5 biopsies (pre- and post-treatment) were collected. Adverse events included @entity882 , liver enzymopathies, fever, and @entity1333 . Correlation between interferon (IFN)-y induction, adverse events, and NHS-IL12 exposure (maximum concentration and area under the concentration-time curve) were dose-dependent. Serum @entity14121 levels and intratumoral CD8+ populations increased after treatment. Partial responses, according to Response Evaluation Criteria in @entity5 (RECIST) criteria, were observed in two @entity235 treated with NHS-IL12 0.8 mg/m2 and 1.6 mg/m2. CONCLUSIONS/SIGNIFICANCE: NHS-IL12 was administered safely to @entity235 with @entity320 and both immunologic and clinical activity was observed. This study successfully defined a narrow therapeutic window for systemic delivery of NHS-IL12 via the subcutaneous route. Results will inform the design and implementation of first-in- @entity1 clinical trials of NHS-IL12 in @entity5 @entity1 .
