title: Neonatal Immune Tolerance Induction to Allow Long-Term Studies With an Immunogenic Therapeutic Monoclonal Antibody in Mice.
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 immune-tolerant 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.
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Piccand
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Juliana
authors.initials: J
authors.lastname: Bessa
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Eginhard
authors.initials: E
authors.lastname: Schick
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Senn
authors.affiliation: Department of Medicine, Université de Fribourg, Chemin du Musée 5, 1700, Fribourg, Switzerland.
authors.forename: Carole
authors.initials: C
authors.lastname: Bourquin
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland. wolfgang.richter@roche.com.|Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland. wolfgang.richter@roche.com.
authors.forename: Wolfgang F
authors.initials: WF
authors.lastname: Richter
mesh_terms: D000068879:Adalimumab / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000097:blood / Q000276:immunology*; D000917:Antibody Formation / Q000187:drug effects* / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000097:blood / Q000139:chemically induced / Q000276:immunology; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D000068879:Adalimumab
keywords: anti-drug antibodies; clearance change; neonatal immune tolerance induction; tolerogen