Neonatal Immune Tolerance Induction to Allow Long-Term Studies With an Immunogenic Therapeutic Monoclonal Antibody in Mice

Abstract

Abstract. The purpose of this study is to test the feasibility of neonatal immune tolerance induction in mice to enable long-term pharmacokinetic studies with immunogenic therapeutic monoclonal antibodies (mAb). Neonatal immune tolerance was induced by transfer of a mAb to neonatal mice via colostrum from nursing mother mice treated with two subcutaneous doses of a tolerogen starting within the first 24 h after delivery. Adalimumab and efalizumab were administered as tolerogens at various dose levels. Tolerance induction was evaluated in the offspring after reaching adulthood at 8 weeks of age. After a single intravenous injection of the same mAb as used for tolerance induction, the pharmacokinetics of the mAb and formation of anti-drug antibodies (ADA) in plasma were assessed using ELISA. Tolerance induction to adalimumab was achieved in a maternal dose-dependent manner. Adalimumab immunetolerant offspring showed a slower adalimumab clearance (4.24±0.32 mL/day/kg) as compared to the control group (12.09±3.81 mL/day/kg). In the control group, accelerated clearance started 7 days after adalimumab dosing, whereas immune-tolerant offspring showed a log-linear terminal concentration-time course. In the offspring, the absence of predose ADA levels was indicative of successful tolerance induction. The second test compound efalizumab was not immunogenic in mice under our experimental conditions. Overall, the present study demonstrated the suitability of neonatal immune tolerance induction for a 4-week single dose study in adult mice with a human therapeutic mAb that is otherwise immunogenic in laboratory animals.

Delanzomib, a Novel Proteasome Inhibitor, Combined With Adalimumab Drastically Ameliorates Collagen-Induced Arthritis in Rats by Improving and Prolonging the Anti-TNF-α Effect of Adalimumab

“…The drugs with immunosuppressive effect like methotrexate reduce the production of anti-adalimumab antibodies by suppressing the immune response ( Ducourau et al, 2020 ). In this study, the production of anti-adalimumab antibodies was observed in rats with CIA under the continuous treatment of adalimumab, which was consistent with the results of other study ( Piccand et al, 2016 ). More interestingly, a comparative level of anti-adalimumab antibodies was also observed between the rats in the adalimumab-treated and delanzomib + adalimumab-treated groups, suggesting that delanzomib less affected the expression of anti-adalimumab antibodies.…”

“…The formation of mAb-ADA immune complexes can accelerate the clearance of mAbs via the activation of complement and increased uptake by phagocytic cells and red blood cells ( Schellekens, 2002 ). Although adalimumab is humanized mAbs, adalimumab can still cause immune response to produce anti-adalimumab antibodies in rats due to its immunogenicity for rats ( Piccand et al, 2016 ). The drugs with immunosuppressive effect like methotrexate reduce the production of anti-adalimumab antibodies by suppressing the immune response ( Ducourau et al, 2020 ).…”

Formation and Glomerular Deposition of Immune Complexes in Mice Administered Human Antibodies: Evaluation of Dose, Frequency, and Biomarkers

“…This can most likely be explained by increased aTNFα clearance by the formed ADAs. 1,9,19,40 –46 Additionally, there was an unexplainable high incidence and concentration of ADAs in the vehicle group at week 13 in the dose regimen study as also observed previously. 46 The ADAs might have formed in response to exposure to low levels of aTNFα present at the animal facility 46 ; however, these animals in the present study had no measured aTNFα exposure or increased IC formation or deposition, apart from a low level of cCIC, C3d, and mIgM in IHC staining as incidentally observed in vehicle-administered animals.…”

Ozoralizumab, a Humanized Anti-TNFα NANOBODY® Compound, Exhibits Efficacy Not Only at the Onset of Arthritis in a Human TNF Transgenic Mouse but Also During Secondary Failure of Administration of an Anti-TNFα IgG

“…Heterozygous 6-week-old Tg197 mice were gender-balanced and assigned to two groups for the pharmacokinetic study of adalimumab and ozoralizumab (35)(36)(37). The animals in the adalimumab group (n = 4) and the ozoralizumab group (n = 4) were subcutaneously injected with adalimumab or ozoralizumab both at 1 mg/kg.…”