The Göttingen minipig<sup>®</sup>as an alternative non-rodent species for immunogenicity testing: A demonstrator study using the IL-1 receptor antagonist anakinra

Mierlo, Geertje J. D. van; Cnubben, N.H.P.; Kuper, C. Frieke; Wolthoorn, Jasja; Meeteren-Kreikamp, Angelique P van; Nagtegaal, Machiel M; Doornbos, Robert; Ganderup, Niels-Christian; Penninks, André

doi:10.3109/1547691x.2012.735274

Cited by 18 publications

(14 citation statements)

References 14 publications

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“…The same holds true for immunogenicity results obtained in the minipig using the recombinant human protein anakinra (van Mierlo et al, 2013). For infliximab, no reliable ADA-measurements could be performed, based on the high levels of infliximab detected during the whole study.…”

Section: Resultsmentioning

confidence: 77%

The minipig as an alternative non-rodent model for immunogenicity testing using the TNFα blockers adalimumab and infliximab

Mierlo

Cnubben

Wouters

et al. 2013

Journal of Immunotoxicology

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Immunogenicity is a major issue of concern for monoclonal antibodies used in human diseases and is by default mainly determined in non-human primates (NHP), as target molecules are considered most similar in NHP compared to human. In this manuscript the predictive value of immunogenicity testing in minipigs for human safety is evaluated, as the immune system of the pig is functionally similar to that in other mammalian species. Adalimumab and infliximab (both monoclonal antibodies blocking TNFa) were used as model substances. Female Gö ttingen minipigs (4/group) were treated every other week with low (0.1 mg/kg), mid (1.0 mg/kg), or high dose (5 mg/kg) adalimumab or 5 mg/kg infliximab subcutaneous (SC) over a period of 8 weeks. After first and last dosing, pharmacokinetic analysis was performed. Anti-drug antibodies (ADAs) were measured on several time points. Furthermore, hematology, clinical chemistry, body weight, clinical signs, and histopathology of several organs were evaluated. No signs of toxicity of the treatments were observed in the limited organs and tissues collected. Eleven out of 12 minipigs treated with adalimumab elicited a detectable ADA response. Induction of ADA was correlated with decreased plasma levels of adalimumab. Infliximab clearance was comparable after first and last dose. Therefore, the presence of ADA directed to infliximab was considered highly unlikely. It was concluded that the minipig and NHP showed comparable suitability for immunogenicity prediction in humans. More studies with other biopharmaceutical products are needed to strengthen the status of the minipig as an alternative model for immunotoxicity testing including immunogenicity.

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Section: Resultsmentioning

confidence: 77%

The minipig as an alternative non-rodent model for immunogenicity testing using the TNFα blockers adalimumab and infliximab

Mierlo

Cnubben

Wouters

et al. 2013

Journal of Immunotoxicology

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“…Each group received a single dose of ustekinumab (Stelara ® , Janssen-Cilag International NV) given in a single 1 mg/kg SC injection into the internal inguinal fold in the first group (IF) or external part of the inguinal fold in the second group (EF). Before (at time 0) and after drug administration, blood was sampled from the jugular vein (2 mL) at intervals of 6,12,24,36,48,60,72,84,96,120,144,168,288,384 and 432 h (18 days) after injection into heparinized tubes using a vacutainer (BD Vacutainer ® Safety-Lok) for pharmacokinetics and anti-drug-antibodies (ADA) analysis.…”

Section: Animalsmentioning

confidence: 99%

“…The pig model was investigated in pharmacommetry and toxicology of small molecules and biologics [1][2][3][4]. The value of the pig model has been shown in many studies [5][6][7][8][9]. Due to multiple similarities in the structure and physiology of human and pig skin, this model is very useful for subcutaneous (SC) formulations testing [10].…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Ustekinumab pharmacokinetics after subcutaneous administration in pig

Grabowski¹,

Burmańczuk²,

Derlacz³

et al. 2019

Preprint

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Background. Due to multiple similarities in the structure and physiology of human and pig skin, the pig model is very useful for biological drugs testing after subcutaneous administration. The differences between subcutaneous injection sites could have significant impact on the absorption phase and pharmacokinetic profiles of biologic drugs. The aim of the current study was to analyse pharmacokinetics and selected biochemical and hematological parameters after a single subcutaneous administration of ustekinumab – human therapeutic monoclonal antibody, in regular pigs and compare parameters following administration into external or internal regions of the inguinal fold. The subjects were 12 healthy female large white piglets. Each group received a single dose of ustekinumab given in a 1 mg/kg subcutaneous injection into the internal inguinal fold or external part of the inguinal fold. Results. An analysis of hematological parameters showed that a single subcutaneous dose of ustekinumab at dose 1 mg/kg of body weight in pigs does not cause changes in the hematological parameters that go beyond the physiological limits. The differences in absorption rate between the internal inguinal fold or external part of the inguinal fold were not significant. However the time of maximal concentration, clearance, area under the curve calculated between zero and mean residence time and mean residence time between groups were substantially different (p>0.05). The relative bioavailability after external part of the inguinal fold administration was 40.36% lower than after internal inguinal fold ustekinumab administration. Conclusions. Breeding pig has been shown to be a relevant pharmacokinetics model to study subcutaneously administered ustekinumab.

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“…Limitations for the use of NHP in regulatory toxicology studies have opened discussions on the suitability of using minipigs in drug development studies [157]. Recently, it was shown that minipigs are comparable to NHP in immunogenicity testing [158,159] and their liver metabolism is similar to that of humans [160]. Additionally, models of porcine osteoporosis have been developed to expand the usefulness of this species for bone research [161][162][163][164].…”

Section: Pigmentioning

confidence: 99%

The rational use of animal models in the evaluation of novel bone regenerative therapies

Perić¹,

Dumić-Čule²,

Grčević³

et al. 2015

Bone

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The Göttingen minipig^®as an alternative non-rodent species for immunogenicity testing: A demonstrator study using the IL-1 receptor antagonist anakinra

Cited by 18 publications

References 14 publications

The minipig as an alternative non-rodent model for immunogenicity testing using the TNFα blockers adalimumab and infliximab

The minipig as an alternative non-rodent model for immunogenicity testing using the TNFα blockers adalimumab and infliximab

WITHDRAWN: Ustekinumab pharmacokinetics after subcutaneous administration in pig

The rational use of animal models in the evaluation of novel bone regenerative therapies

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The Göttingen minipig®as an alternative non-rodent species for immunogenicity testing: A demonstrator study using the IL-1 receptor antagonist anakinra

Cited by 18 publications

References 14 publications

The minipig as an alternative non-rodent model for immunogenicity testing using the TNFα blockers adalimumab and infliximab

The minipig as an alternative non-rodent model for immunogenicity testing using the TNFα blockers adalimumab and infliximab

WITHDRAWN: Ustekinumab pharmacokinetics after subcutaneous administration in pig

The rational use of animal models in the evaluation of novel bone regenerative therapies

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The Göttingen minipig^®as an alternative non-rodent species for immunogenicity testing: A demonstrator study using the IL-1 receptor antagonist anakinra