Incidences and Range of Spontaneous Findings in Control Cynomolgus Monkeys (<i>Macaca fascicularis</i>) Used in Toxicity Studies

Chamanza, Ronnie; Marxfeld, Heike; Blanco, Ana Isabel Cos; Naylor, Stuart W.; Bradley, Alys

doi:10.1177/0192623310368981

Cited by 136 publications

(174 citation statements)

References 27 publications

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“…However, animals that received 0.01 PFU of low-particle/PFU virus did not exhibit any petechial cutaneous rash or pale liver and/or spleen. Animals receiving any dose of the high-particle/PFU virus and those receiving 1 or 100 PFU of low-particle/PFU virus also had lesions consistent with Ebola virus-induced hemorrhagic fever (29)(30)(31). Histologically significant lesions present in animals that succumbed to acute EBOV infection included lymphoid depletion and necrosis within spleen and lymph nodes, splenic fibrin deposition, and piecemeal hepatocellular necrosis.…”

Section: Effects Of Ebov Specific Infectivity During In Vivo Infectionmentioning

confidence: 96%

Particle-to-PFU Ratio of Ebola Virus Influences Disease Course and Survival in Cynomolgus Macaques

Alfson

Avena

Beadles

et al. 2015

J Virol

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This study addresses the role of Ebola virus (EBOV) specific infectivity in virulence. Filoviruses are highly lethal, enveloped, single-stranded negative-sense RNA viruses that can cause hemorrhagic fever. No approved vaccines or therapies exist for filovirus infections, and infectious virus must be handled in maximum containment. Efficacy testing of countermeasures, in addition to investigations of pathogenicity and immune response, often requires a well-characterized animal model. For EBOV, an obstacle in performing accurate disease modeling is a poor understanding of what constitutes an infectious dose in animal models. One well-recognized consequence of viral passage in cell culture is a change in specific infectivity, often measured as a particle-to-PFU ratio. Here, we report that serial passages of EBOV in cell culture resulted in a decrease in particle-to-PFU ratio. Notably, this correlated with decreased potency in a lethal cynomolgus macaque (Macaca fascicularis) model of infection; animals were infected with the same viral dose as determined by plaque assay, but animals that received more virus particles exhibited increased disease. This suggests that some particles are unable to form a plaque in a cell culture assay but are able to result in lethal disease in vivo. These results have a significant impact on how future studies are designed to model EBOV disease and test countermeasures. IMPORTANCEEbola virus (EBOV) can cause severe hemorrhagic disease with a high case-fatality rate, and there are no approved vaccines or therapies. Specific infectivity can be considered the total number of viral particles per PFU, and its impact on disease is poorly understood. In stocks of most mammalian viruses, there are particles that are unable to complete an infectious cycle or unable to cause cell pathology in cultured cells. We asked if these particles cause disease in nonhuman primates by infecting monkeys with equal infectious doses of genetically identical stocks possessing either high or low specific infectivities. Interestingly, some particles that did not yield plaques in cell culture assays were able to result in lethal disease in vivo. Furthermore, the number of PFU needed to induce lethal disease in animals was very low. Our results have a significant impact on how future studies are designed to model EBOV disease and test countermeasures.

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Section: Effects Of Ebov Specific Infectivity During In Vivo Infectionmentioning

confidence: 96%

Particle-to-PFU Ratio of Ebola Virus Influences Disease Course and Survival in Cynomolgus Macaques

Alfson

Avena

Beadles

et al. 2015

J Virol

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“…The body weights of study animals increased during these studies and no adverse effects were apparent in the clinical and anatomic pathology parameters evaluated. Sporadic changes that occurred in food consumption and fecal consistency were transient and considered typical for institutional macaque colonies (40). Rats were observed predose, on the day of dose administration, and for up to 57 days postdose, as determined empirically by T-cell cSEMA4D desaturation.…”

Section: Toxicology Assessmentsmentioning

confidence: 99%

Nonclinical Safety Evaluation of VX15/2503, a Humanized IgG4 Anti-SEMA4D Antibody

Leonard

Fisher

Winter

et al. 2015

Molecular Cancer Therapeutics

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The humanized IgG4 monoclonal antibody VX15/2503 bound with 1 to 5 nmol/L affinity to purified recombinant semaphorin 4D (SEMA4D; CD100) produced using murine, rat, cynomolgus macaque, and human sequences. The affinity for native SEMA4D expressed on macaque T lymphocytes was approximately 0.6 nmol/L. Tissues from rats and cynomolgus macaques demonstrated specific staining only with resident lymphocytes. Singledose and one-month toxicology/PK studies used VX15/2503 dose levels of 0 to 100 mg/kg. No toxicity was observed with either species in these studies, thus the no observed adverse effect level (NOAEL) was 100 mg/kg. C max , exposure, and half-life values were similar for both rats and macaques. The NOAEL in a primate maximum feasible dose study was 200 mg/kg. Saturation of Tcell-associated SEMA4D occurred following administration of single doses of 0.1 mg/kg and above; five weekly injections of VX15/2503 at a dose level of 100 mg/kg produced saturation lasting for more than 120 and 130 days, respectively, for rats and primates. Macaques administered five weekly doses of VX15/2503 showed dose-dependent reductions of 2-to 3-fold in T-cell SEMA4D (cSEMA4D) expression levels compared with controls. Reduced cSEMA4D expression levels continued until serum antibody concentrations were 2 to 5 mg/mL, and thereafter normal cSEMA4D levels were restored. On the basis of these data, a phase I clinical study of the safety and tolerability of VX15/2503 was conducted, enrolling adult patients with advanced solid tumor diseases; a single-dose, dose escalation, phase I safety study was also initiated with subjects with multiple sclerosis.

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“…Comparable cardiac abnormalities have been reported by 5 groups in studies that involved up to 510 normal, untreated cynomolgus monkeys, suggesting that these changes were unrelated to Hu-Mik␤1. [34][35][36][37] …”

Section: Preclinical Hu-mik␤1 Toxicologymentioning

confidence: 99%

Phase 1 trial of IL-15 trans presentation blockade using humanized Mik-Beta-1 mAb in patients with T-cell large granular lymphocytic leukemia

Waldmann

Conlon

Stewart

et al. 2013

Blood

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Incidences and Range of Spontaneous Findings in Control Cynomolgus Monkeys (Macaca fascicularis) Used in Toxicity Studies

Cited by 136 publications

References 27 publications

Particle-to-PFU Ratio of Ebola Virus Influences Disease Course and Survival in Cynomolgus Macaques

Particle-to-PFU Ratio of Ebola Virus Influences Disease Course and Survival in Cynomolgus Macaques

Nonclinical Safety Evaluation of VX15/2503, a Humanized IgG4 Anti-SEMA4D Antibody

Phase 1 trial of IL-15 trans presentation blockade using humanized Mik-Beta-1 mAb in patients with T-cell large granular lymphocytic leukemia

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