"Simulect" as a model compound for assessing placental transfer of monoclonal antibodies in minipigs.

The aim of this study was to directly test and measure in vivo, if placental transfer of monoclonal antibodies takes place in pregnant Göttingen Minipigs to assess their suitability for reproductive assessment of therapeutic monoclonal antibodies. Simulect®, an approved anti CD25 (anti IL-2 receptor alpha) chimeric monoclonal IgG1 antibody, was used as a model monoclonal antibody. Maternal systemic exposure and potential placental transfer of Simulect® to fetuses were investigated following 4 weekly bolus intravenous administration of 5.0 mg/kg from gestation day (GD) 79 or 80 (e.g GD 79, 86, 93 and 100) and with terminal Caesarean section on GD 108 or GD 109 respectively. Results clearly showed exposure in maternal animals, detectable compound in the amniotic fluid from one out of 9 maternal animals, but no exposure in fetuses confirming absence of placental transfer of the selected model antibody Simulect® in minipigs. The absence of Simulect® in the fetuses further supports that the presence of Simulect® in the amniotic fluid in one maternal animal was likely due to contamination with maternal blood during sampling. The demonstrated absence of fetal exposure clearly indicates that, the minipig is not a suitable species for conduct of reproductive toxicity studies with monoclonal antibodies.

Age- and Sex-Associated Effects on Acute-Phase Proteins in Göttingen Minipigs.

Göttingen minipigs are a useful model for diseases having an inflammatory component, and the associated use of acute-phase proteins (APP) as biomarkers of inflammation warrants establishment of their reference ranges. The objective of this study was to establish reference values for selected APP in Göttingen minipigs and to investigate the effects of age, sex, and various stimuli on these ranges. Serum concentrations of C-reactive protein (CRP), serum amyloid A (SAA), haptoglobin, pig major acute-phase protein (PMAP), albumin, and porcine α-1 acid glycoprotein (PAGP) were evaluated in 4 age groups (6, 16, 24 and 40-48 wk) of male and female Göttingen minipigs. In addition, minipigs were tested under 2 housing conditions, after acute LPS challenge, and after diet-induced obesity with and without mild diabetes. Changing the pigs to a new environment induced significant increases in CRP, PMAP, haptoglobin and PAGP and a decrease in albumin. An acute LPS stimulus increased CRP, PMAP, haptoglobin, and SAA; PAGP was unchanged and albumin decreased. Obese pigs with and without diabetes showed increases in CRP and PAGP, albumin decreased, and haptoglobin and SAA were unchanged. PMAP was increased only in obese pigs without diabetes. In conclusion, reference values for CRP, PMAP, haptoglobin, SAA, PAGP and albumin were established for male and female Göttingen minipigs of different ages. These APP were influenced by age and sex, underlining the importance of considering these factors when designing and interpreting studies including aspects of inflammation. In addition, an APP response was verified after both acute and chronic stimuli.

A hereditary disposition for bovine peripheral nerve sheath tumors in Danish Holstein cattle.

BACKGROUND: Peripheral nerve sheath tumors (PNSTs) are frequently found in Danish cattle at slaughter. Bovine PNSTs share several gross and histopathological characteristics with the PNSTs in humans with heritable neurofibromatosis syndromes. The aim of the present study was to investigate a possible hereditary disposition to PNSTs in dairy cattle by statistical analysis performed on data from 567 cattle with PNSTs. Furthermore, a preliminary genome-wide association study (GWAS) was performed on DNA isolated from 28 affected and 28 non-affected Holstein cows to identify loci in the bovine genome involved in the development of PNSTs. RESULTS: PNSTs were significantly more common in the Danish Holstein breed than in other breeds with 0.49% of Danish Holsteins slaughtered during an eight-year-period having PNSTs. PNSTs also occurred significantly more frequently in the offspring of some specific Holstein sires. Examination of three generation pedigrees showed that these sires were genetically related through a widely used US Holstein sire. The PNSTs included in GWAS were histologically classified as neurofibroma-schwannoma (43%), schwannoma (36%) and neurofibroma (21%) and derived from Holstein cows with multiple PNSTs. A single SNP on chromosome 27 reached genome-wide significance. CONCLUSIONS: Gross and histological characteristics of bovine PNSTs are comparable to PNSTs in humans (schwannomatosis). Danish Holsteins are genetically disposed to develop PNSTs but the examined materials are insufficient to allow determination of the mode of inheritance.