Satoru Oneda

Development in the cynomolgus macaque following administration of ustekinumab, a human anti‐il‐12/23p40 monoclonal antibody, during pregnancy and lactation

BACKGROUND Ustekinumab is a human monoclonal antibody that binds to the p40 subunit of interleukin (IL) 12 and IL-23 and inhibits their pharmacological activity. To evaluate potential effects of ustekinumab treatment during pregnancy, developmental studies were conducted in cynomolgus macaques. METHODS Ustekinumab was tested in two embryo/fetal development (EFD) studies and in a combined EFD/pre and postnatal development (PPND) study. In the EFD studies, pregnant macaques (12/group) were dosed with saline or ustekinumab (9 mg/kg IV, 22.5 mg/kg SC, or 45 mg/kg IV or SC during the period of major organogenesis, gestation day [GD] 20-50). Fetuses were harvested on GD100-102 and examined for any effects on development. In the EFD/PPND study, pregnant macaques were injected with saline or ustekinumab (22.5 or 45 mg/kg SC) from GD20 through lactation day 33. Infants were examined from birth through 6 months of age for morphological and functional development. Potential effects on the immune system were evaluated by immunophenotyping of peripheral blood lymphocytes and immunohistopathology of lymphoid tissues in fetuses and infants and by T-dependent antibody response (TDAR) to KLH and TTX and by DTH response in infants. Ustekinumab concentrations were measured in serum from dams, fetus, and infants and in breast milk. RESULTS Ustekinumab treatment produced no maternal toxicity and no toxicity in the fetuses or infants, including no effects on the TDAR or DTH responses. Ustekinumab was present in serum from GD100 fetuses and was present in infant serum through day 120 post-birth. Low levels of ustekinumab were present in breast milk. CONCLUSIONS Exposure of macaque fetuses and infants to ustekinumab had no adverse effects on pre- and postnatal development.

Embryo/fetal development in cynomolgus monkeys exposed to natalizumab, an α4 integrin inhibitor

BACKGROUND Natalizumab is a humanized monoclonal immunoglobulin G4 antibody to human alpha4 integrin that binds to the alpha4 subunit of alpha4beta1 and alpha4beta7 integrins, where it blocks the interaction of these integrins with their ligands, including fibronectin, vascular cell adhesion molecule-1, and mucosal addressin cellular adhesion molecule-1. Because alpha4 integrins and their ligands appear to be involved in mammalian fetal development, it is possible that natalizumab may interfere with these processes. METHODS The effects of natalizumab on fetal development were assessed in cynomolgus monkeys at doses of 0, 3, 10, and 30 mg/kg administered intravenously every other day from gestational day (GD) 20 to 70. Pregnancies were terminated by Cesarean section at GD 100. RESULTS Natalizumab treatment was not associated with increased abortions. All fetuses were alive. No external, visceral, or skeletal abnormalities were seen that were considered to be related to treatment with natalizumab. No histopathological findings were seen in the heart, a target organ of developmental toxicity with a small molecule inhibitor of alpha4 integrin. At dose levels > or = 10 mg/kg, hematological and/or lymphoid effects were observed in some fetuses, consisting of slight thymic atropy, increased extramedullary hematopoiesis in the spleen with a corresponding decrease in the liver, increases in WBC and nucleated RBC, decreases in RBC parameters, and decreases in lymphoid CD20 staining. CONCLUSION Natalizumab had no abortifacient or teratogenic effects, but was associated with changes in fetal hematopoiesis and leukocyte trafficking.

Embryo-fetal developmental toxicity of figitumumab, an anti-insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibody, in cynomolgus monkeys.

BACKGROUND Insulin-like growth factor (IGF) signaling has been linked to tumor cell survival and tumorigenesis. The anti-IGF-1 receptor monoclonal antibody, figitumumab, has been developed as an anti-cancer therapeutic. As part of the safety evaluation, an embryo-fetal developmental toxicity study was conducted in the cynomolgus monkey. METHODS Figitumumab was administered once weekly intravenously at a dose of 5, 15, or 100 mg/kg during the period of major organogenesis (gestation days [GD] 20-48) with scheduled cesarean section around GD100. Maternal endpoints included clinical observations, food consumption, body weights, hematology, placental weights, toxicokinetics, and immunogenicity. Fetal evaluations included viability; body weights; external, visceral, and skeletal examination (and measurements); drug exposure; and immunogenicity. RESULTS There was a dose-dependent increase in embryo-fetal loss in the presence of decreased maternal food consumption and slight reduction in body weight. Figitumumab-related embryo-fetal developmental toxicity was observed as growth retardation exhibited by reduced fetal body weights at all doses with corresponding developmental delays in morphology. Treatment-related fetal structural malformations were also observed in the mid- and high-dose groups. CONCLUSIONS Maternal figitumumab dosing only during the period of organogenesis was associated with pregnancy loss and fetal growth deficits; both considered consistent with inhibition of IGF signaling. Fetal malformations were also observed, and were considered secondary to altered placental function and/or reduced fetal growth; however, direct inhibition of IGF signaling in the conceptus cannot be ruled out. This appears to be the first report of treatment-related fetal anomalies with a monoclonal antibody when administered only during the period of major organogenesis.

Morphologic, Stereologic, and Morphometric Evaluation of the Nervous System in Young Cynomolgus Monkeys (Macaca fascicularis) Following Maternal Administration of Tanezumab, a Monoclonal Antibody to Nerve Growth Factor

Tanezumab, an antibody to nerve growth factor, was administered to pregnant cynomolgus monkeys at 0, 0.5, 4, and 30 mg/kg weekly, beginning gestation day (GD) 20 through parturition (∼GD165). Maternal tanezumab administration appeared to increase stillbirths and infant mortality, but no consistent pattern of gross and/or microscopic change was detected to explain the mortality. Offspring exposed in utero were evaluated at 12 months of age using light microscopy (all tissues), stereology (basal forebrain cholinergic and dorsal root ganglia neurons), and morphometry (sural nerve). Light microscopy revealed decreased number of neurons in sympathetic ganglia (superior mesenteric, cervicothoracic, and ganglia in the thoracic sympathetic trunk). Stereologic assessment indicated an overall decrease in dorsal root ganglion (thoracic) volume and number of neurons in animals exposed to tanezumab 4 mg/kg (n = 9) and 30 mg/kg (n = 1). At all tanezumab doses, the sural nerve was small due to decreases in myelinated and unmyelinated axons. Existing axons/myelin sheaths appeared normal when viewed with light and transmission electron microscopy. There was no indication of tanezumab-related, active neuron/nerve fiber degeneration/necrosis in any tissue, indicating decreased sensory/sympathetic neurons and axonal changes were due to hypoplasia or atrophy. These changes in the sensory and sympathetic portions of the peripheral nervous system suggest some degree of developmental neurotoxicity, although what effect, if any, the changes had on normal function and survival was not apparent. Overall, these changes were consistent with published data from rodent studies.

Developmental toxicity assessment of tanezumab, an anti-nerve growth factor monoclonal antibody, in cynomolgus monkeys (Macaca fascicularis).

Two intravenous studies with tanezumab, an anti-nerve growth factor monoclonal antibody, were conducted in pregnant cynomolgus monkeys to assess potential effects on pregnancy and pre- and postnatal development. Study 1 evaluated infants up to 12 months of age following weekly maternal dosing (0, 0.5, 4 or 30 mg/kg; 18 per group) from gestation day (GD) 20 through parturition. Study 2 evaluated infants 2 months postnatally following weekly maternal dosing (0, 0.5 or 30 mg/kg; 20-21 per group) from GD 20 through 48. In the absence of maternal toxicity, tanezumab increased stillbirth and post-birth infant mortality/morbidity, decreased infant growth and resulted in microscopic changes in the peripheral sympathetic and sensory nervous system of the infants at all doses. Decreased primary antibody responses and increased incidences in skin changes in infants were also observed. The no-observed-adverse-effect-level for maternal toxicity was 30 mg/kg and <0.5 mg/kg for developmental toxicity.

Object discrimination and reversal learning in infant and juvenile non-human primates in a non-clinical laboratory

Biopharmaceutical development necessitates use of non‐human primates in toxicology, leading to adoption of non‐traditional methods including cognitive function assessment.