title: Enhancement of humoral and cellular immunity with an anti-glucocorticoid-induced tumour necrosis factor receptor monoclonal antibody.
abstract: Adjuvants, including antibodies to tumour necrosis factor receptor superfamily members, augment immune responses. One member of this family, glucocorticoid-induced tumour necrosis factor receptor (GITR), is expressed at low levels on naive/resting T cells, B cells and macrophages, but at higher levels on T regulatory cells. The aim of this study was to determine the ability of a rat anti-mouse GITR monoclonal antibody, 2F8, to stimulate murine humoral and cellular immunity in a prime boost model with particular attention to posology and antigen-specific effects. 2F8 enhanced the humoral immune response to ovalbumin and haemagglutinin (HA) compared with controls and this enhancement was equal to or greater than that obtained in mice dosed with standard adjuvants. 2F8 F(ab')(2) fragments were as effective as intact antibody in boosting humoral immunity, indicating that FcR-mediated cross-linking of 2F8 is not required for efficacy. Moreover, the enhanced response was durable and antigen specific. Administration of 2F8 shifted the immune response towards a T helper type 1 response with significant enhancement of immunoglobulin G2a- and G2b-specific anti-HA antibodies, as well as enhanced cellular immunity as measured by ELISPOT. 2F8-treated mice also generated significantly more neutralizing antibodies to HA than control mice. Our findings show that anti-GITR is a robust, versatile adjuvant that, unlike commonly used adjuvants that primarily enhance humoral immunity, enhances both humoral and cellular immunity. These results support the continued development of anti-GITR for such indications as haematological and solid tumours, chronic viral infections, and as a vaccine adjuvant.
authors.affiliation: Tolerx, Inc., 300 Technology Square, Cambridge, MA 02139, USA. jponte@tolerx.com
authors.forename: Jose F
authors.initials: JF
authors.lastname: Ponte
authors.forename: Paul
authors.initials: P
authors.lastname: Ponath
authors.forename: Reema
authors.initials: R
authors.lastname: Gulati
authors.forename: Michael
authors.initials: M
authors.lastname: Slavonic
authors.forename: Michael
authors.initials: M
authors.lastname: Paglia
authors.forename: Adam
authors.initials: A
authors.lastname: O'Shea
authors.forename: Masahide
authors.initials: M
authors.lastname: Tone
authors.forename: Herman
authors.initials: H
authors.lastname: Waldmann
authors.forename: Louis
authors.initials: L
authors.lastname: Vaickus
authors.forename: Michael
authors.initials: M
authors.lastname: Rosenzweig
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000276:immunology*; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006388:Hemagglutinins / Q000276:immunology / Q000494:pharmacology; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology; D056724:Immunity, Humoral / Q000187:drug effects*; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000494:pharmacology; D007074:Immunoglobulin G / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D051381:Rats; D017475:Receptors, Nerve Growth Factor / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006388:Hemagglutinins; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; D010047:Ovalbumin