title: Tofacitinib suppresses antibody responses to protein therapeutics in murine hosts.
abstract: Immunogenicity remains the "Achilles' heel" of protein-based therapeutics. Anti-drug Abs produced in response to protein therapeutics can severely limit both the safety and efficacy of this expanding class of agent. In this article, we report that monotherapy of mice with tofacitinib (the JAK inhibitor) quells Ab responses to an immunotoxin derived from the bacterial protein Pseudomonas exotoxin A, as well as to the model Ag keyhole limpet hemocyanin. Thousand-fold reductions in IgG1 titers to both Ags were observed 21 d post immunization. In fact, suppression was evident for all IgG isotypes and IgM. A reduction in IgG3 production was also noted with a thymus-independent type II Ag. Mechanistic investigations revealed that tofacitinib treatment led to reduced numbers of CD127+ pro-B cells. Furthermore, we observed fewer germinal center B cells and the impaired formation of germinal centers of mice treated with tofacitinib. Because normal Ig levels were still present during tofacitinib treatment, this agent specifically reduced anti-drug Abs, thus preserving the potential efficacy of biological therapeutics, including those used as cancer therapeutics.
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; ondam@mail.nih.gov fitzgerd@helix.nih.gov.
authors.forename: Masanori
authors.initials: M
authors.lastname: Onda
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Kamran
authors.initials: K
authors.lastname: Ghoreschi
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Scott
authors.initials: S
authors.lastname: Steward-Tharp
authors.affiliation: Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Craig
authors.initials: C
authors.lastname: Thomas
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Shea
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Ira H
authors.initials: IH
authors.lastname: Pastan
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: David J
authors.initials: DJ
authors.lastname: FitzGerald
mesh_terms: D036002:ADP Ribose Transferases / Q000494:pharmacology*; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects*; D001402:B-Lymphocytes / Q000276:immunology; D001427:Bacterial Toxins / Q000494:pharmacology*; D005098:Exotoxins / Q000494:pharmacology*; D005260:Female; D018858:Germinal Center / Q000276:immunology; D006433:Hemocyanins / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D000922:Immunotoxins / Q000494:pharmacology*; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010880:Piperidines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D037521:Virulence Factors / Q000494:pharmacology*; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D005098:Exotoxins; D006433:Hemocyanins; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D000922:Immunotoxins; D053612:Janus Kinases; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C479163:tofacitinib; C032808:keyhole-limpet hemocyanin