The severity grade is an important component of a histopathologic diagnosis in a nonclinical toxicity study that helps distinguish treatment-related effects from background findings and aids in determining adverse dose levels during hazard characterization. Severity grades should be assigned based only on the extent (i.e., amount and complexity) of the morphologic change in the examined tissue section(s) and be clearly defined in the pathology report for critical lesions impacting study interpretation. However, the level of detail provided and criteria by which severity grades are assigned can vary, which can lead to inappropriate comparisons and confusion when evaluating pathology results. To help address this issue, a Working Group of the Society of Toxicologic Pathology's Scientific and Regulatory Policy Committee was formed to provide a "points to consider" article on the assignment and application of pathology severity grades. Overall, the Working Group supports greater transparency and consistency in the reporting of grading scales and provides recommendations to improve selection of diagnoses requiring more detailed severity criteria. This information should enhance the overall understanding by toxicologic pathologists, toxicologists, and regulatory reviewers of pathology findings and thereby improve effective communication in regulatory submissions.

A monoclonal antibody (mAb) against the blood-brain barrier (BBB) transferrin receptor (TfR) is a potential agent for delivery of biologic drugs to the brain across the BBB. However, to date, no TfRMAb has been tested with chronic dosing in a primate model. A humanized TfRMAb against the human (h) TfR1, which cross reacts with the primate TfR, was genetically engineered with high affinity (ED50 = 0.18 ± 0.04 nM) for the human TfR type 1 (TfR1). For acute dosing, the hTfRMAb was tritiated and injected intravenously (IV) in the Rhesus monkey, which confirmed rapid delivery of the humanized hTfRMAb into both brain parenchyma, via transport across the BBB, and into cerebrospinal fluid (CSF), via transport across the choroid plexus. For chronic dosing, a total of 8 adult Rhesus monkeys (4 males, 4 females) were treated twice weekly for 4 weeks with 0, 3, 10, or 30 mg/kg of the humanized hTfRMAb via a 60 min IV infusion for a total of 8 doses prior to euthanasia and microscopic examination of brain and peripheral organs. A pharmacokinetics analysis showed the plasma clearance of the hTfRMAb in the primate was nonlinear, and plasma clearance was increased over 20-fold with chronic treatment of the low dose, 3 mg/kg, of the antibody. Chronic treatment of the primates with the 30 mg/kg dose caused anemia associated with suppressed blood reticulocytes. Immunohistochemistry of terminal brain tissue showed microglia activation, based on enhanced IBA1 immuno-staining, in conjunction with astrogliosis, based on increased GFAP immuno-staining. Moderate axonal/myelin degeneration was observed in the sciatic nerve. Further studies need to be conducted to determine if this neuropathology is induced by the antibody effector function, or is an intrinsic property of targeting the TfR in brain. The results indicate that chronic treatment of Rhesus monkeys with a humanized hTfRMAb may have a narrow therapeutic index, with associated toxicity related to microglial activation and astrogliosis of the brain.

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Abstract.A 2-year-old female Miniature Horse that presented with a history of progressive weight loss, depression, and diarrhea was diagnosed at necropsy with a highly malignant abdominal neoplasm involving the left ovary, kidneys, adrenal glands, intestines, and various abdominal and thoracic lymph nodes. Microscopic examination of these masses revealed large pleomorphic cells that stained positive for vimentin and inhibin and negative for epithelial membrane antigen and placental alkaline phosphatase. Ultrastructural examination of the cells revealed a high nucleocytoplasmic ratio and indented euchromatic nuclei with large nucleoli. Based on the gross, microscopic, immunohistochemical, and ultrastructural features, the neoplasm was identified as a malignant granulosa-theca cell tumor, a rare neoplasm in young horses.