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Summary PAC-1 is a preferential small molecule activator of procaspase-3 and has potential to become a novel and effective anticancer agent. The rational development of PAC-1 for translational oncologic applications would be advanced by coupling relevant in vitro cytotoxicity studies with pharmacokinetic investigations conducted in large mammalian models possessing similar metabolism and physiology as people. In the present study, we investigated whether concentrations and exposure durations of PAC-1 that induce cytotoxicity in lymphoma cell lines in vitro can be achievable in healthy dogs through a constant rate infusion (CRI) intravenous delivery strategy. Time- and dose-dependent procaspase-3 activation by PAC-1 with subsequent cytotoxicity was determined in a panel of B-cell lymphoma cells in vitro. The pharmacokinetics of PAC-1 administered orally or intravenously was studied in 6 healthy dogs using a crossover design. The feasibility of maintaining steady state plasma concentration of PAC-1 for 24 or 48 h that paralleled in vitro cytotoxic concentrations was investigated in 4 healthy dogs. In vitro, PAC-1 induced apoptosis in lymphoma cell lines in a time- and dose-dependent manner. The oral bioavailability of PAC-1 was relatively low and highly variable (17.8 ± 9.5%). The achievement and maintenance of predicted PAC-1 cytotoxic concentrations in normal dogs was safely attained via intravenous CRI lasting for 24 or 48 h in duration. Using the dog as a large mammalian model, PAC-1 can be safely administered as an intravenous CRI while achieving predicted in vitro cytotoxic concentrations.

PAC-1 is a preferential small molecule activator of procaspase-3 and has potential to become a novel and effective anticancer agent. The rational development of PAC-1 for translational oncologic applications would be advanced by coupling relevant in vitro cytotoxicity studies with pharmacokinetic investigations conducted in large mammalian models possessing similar metabolism and physiology as people. In the present study, we investigated whether concentrations and exposure durations of PAC-1 that induce cytotoxicity in lymphoma cell lines in vitro can be achievable in healthy dogs through a constant rate infusion (CRI) intravenous delivery strategy. Time- and dose-dependent procaspase-3 activation by PAC-1 with subsequent cytotoxicity was determined in a panel of B-cell lymphoma cells in vitro. The pharmacokinetics of PAC-1 administered orally or intravenously was studied in 6 healthy dogs using a crossover design. The feasibility of maintaining steady state plasma concentration of PAC-1 for 24 or 48 hours that paralleled in vitro cytotoxic concentrations was investigated in 4 healthy dogs. In vitro, PAC-1 induced apoptosis in lymphoma cell lines in a time- and dose-dependent manner. The oral bioavailability of PAC-1 was relatively low and highly variable (17.8 ± 9.5%). The achievement and maintenance of predicted PAC-1 cytotoxic concentrations in normal dogs was safely attained via intravenous CRI lasting for 24 or 48 hours in duration. Using the dog as a large mammalian model, PAC-1 can be safely administered as an intravenous CRI while achieving predicted in vitro cytotoxic concentrations.

Foodborne illness source attribution is foundational to a risk-based food safety system. We describe a method for attributing US foodborne illnesses caused by nontyphoidal Salmonella enterica, Escherichia coli O157, Listeria monocytogenes, and Campylobacter to 17 food categories using statistical modeling of outbreak data. This method adjusts for epidemiologic factors associated with outbreak size, down-weights older outbreaks, and estimates credibility intervals. On the basis of 952 reported outbreaks and 32,802 illnesses during 1998-2012, we attribute 77% of foodborne Salmonella illnesses to 7 food categories (seeded vegetables, eggs, chicken, other produce, pork, beef, and fruits), 82% of E. coli O157 illnesses to beef and vegetable row crops, 81% of L. monocytogenes illnesses to fruits and dairy, and 74% of Campylobacter illnesses to dairy and chicken. However, because Campylobacter outbreaks probably overrepresent dairy as a source of nonoutbreak campylobacteriosis, we caution against using these Campylobacter attribution estimates without further adjustment.

BackgroundCanine oral malignant melanoma is an aggressive neoplasm with limited therapeutic options and a median survival of approximately three months in advanced-stage disease. JEN-101 is a protein-engineered interleukin-12 (IL-12) designed for intratumoral delivery and local retention through binding to deposited aluminum hydroxide. Here, we evaluated the safety, tolerability, immunologic, and cytoreductive activity of intratumoral JEN-101 in dogs with spontaneous melanoma. We report findings from the initial weight-based dose-escalation cohort and an expanded cohort where JEN-101 was administered using a tumor volume dosing strategy.MethodsThe clinical study was approved by the University of Illinois IACUC, conducted at the College of Veterinary Medicine, and all pet owners provided written informed consent. The primary objective was to evaluate safety and tolerability of intratumoral JEN-101 in dogs with advanced-stage malignant melanoma. An initial 3+3 dose-escalation design was employed, testing four dose levels (1, 3, 10, and 20 µg/kg) administered intratumorally every three weeks for up to four cycles. In the absence of dose-limiting toxicity or progressive disease, a second treatment course of four additional cycles was permitted. Following dose-escalation, an expansion cohort using a tumor volume-normalized dosing strategy was implemented to further investigate safety, cytokine exposure, and local immune responses. Clinical monitoring included adverse event reporting and tumor response evaluation. Blood, serum, and tumor biopsies were collected at baseline and predefined timepoints for pharmacokinetics, multiplex cytokine analysis, immune cell profiling, and transcriptomics. Descriptive statistics were used for data analysis.ResultsTwenty-four dogs were enrolled, and JEN-101 was well tolerated. Documented adverse events included fever, lethargy, and isolated elevated liver enzymes. Treatment-related events were limited to grade 3; no grade 4 events occurred. Nineteen dogs received ≥4 doses, and nine completed all 8 doses. Pharmacokinetic analysis showed dose-related serum cytokine peaks within 8 hours. Weight-based dosing was associated with more consistent systemic exposure to IL-12, IFN-γ, and IL-10 based on AUC measurements. Responding dogs demonstrated increased systemic IFN-γ and IL-10 AUC levels and local recruitment of CD3+ T cells. Increased proinflammatory and antigen-processing gene expression was identified in responding lesions. JEN-101 was well tolerated with evidence of biological and therapeutic activities.ConclusionsJEN-101 was safe and biologically active in dogs with advanced melanoma. Weight-based dosing induced a more robust therapeutic response and greater systemic immune activation compared to tumor volume-based delivery. These findings support continued development of anchored IL-12 immunotherapy in canine melanoma and underscore the value of immunocompetent dog models in guiding human clinical trials (NCT06171750).AcknowledgementsWe are grateful to the patients, dog owners, and referring veterinarians who participated in the clinical trial. The authors wish to thank Karl Dane Wittrup, Professor at MIT for scientific guidance and design input. The authors also wish to thank Cheryl Kent and Gail Iodice for clinical operations support and Saran Vardhanabhuti for biostatistical support. The authors would like to acknowledge Hui Xu, PhD, Huimin Zhang, and Renee Walker at the Tumor Engineering and Phenotyping Shared Resource (TEP-SR) at the Cancer Center at Illinois for assistance with histology and NanoString experiments. The authors would like to thank Gary McNeil from McNeil Scientific Consulting for protein purification and analytical support, teams at ATUM Bio, Beantown Biotech, Charles River Labs, Ichor Life Sciences, VitroVivo Biotech and Certara for their technical and analytical contributions.Ethics ApprovalThe study protocol for the treatment of advanced melanoma in pet dogs was reviewed and approved by the Institutional Animal Care and Use Committee of the University of Illinois at Urbana-Champaign. All pet dog owners provided written informed consent before enrollment in the trial.