title: Characterization of a surrogate murine antibody to model anti-human CD3 therapies.
abstract: Fc-modified anti-human CD3ε monoclonal antibodies (mAbs) are in clinical development for the treatment of autoimmune diseases. These next generation mAbs have completed clinical trials in patients with type-1 diabetes and inflammatory bowel disease demonstrating a narrow therapeutic window. Lowered doses are ineffective, yet higher pharmacologically-active doses cause an undesirable level of adverse events. Thus, there is a critical need for a return to bench research to explore ways of improving clinical outcomes. Indeed, we recently reported that a short course of treatment affords synergy, providing long-term disease amelioration when combining anti-mouse CD3 and anti-mouse tumor necrosis factor mAbs in experimental arthritis. Such strategies may widen the window between risk and benefit; however, to more accurately assess experimentally the biology and pharmacology, reagents that mimic the current development candidates were required. Consequently, we engineered an Fc-modified anti-mouse CD3ε mAb, 2C11-Novi. Here, we report the functional characterization of 2C11-Novi demonstrating that it does not bind FcγR in vitro and elicits little cytokine release in vivo, while maintaining classical pharmacodynamic effects (CD3-TCR downregulation and T cell killing). Furthermore, we observed that oral administration of 2C11-Novi ameliorated progression of remitting-relapsing experimental autoimmune encephalitis in mice, significantly reducing the primary acute and subsequent relapse phase of the disease. With innovative approaches validated in two experimental models of human disease, 2C11-Novi represents a meaningful tool to conduct further mechanistic studies aiming at exploiting the immunoregulatory properties of Fc-modified anti-CD3 therapies via combination therapy using parenteral or oral routes of administration.
authors.affiliation: NovImmune SA, Plan-Les-Ouates, Switzerland.
authors.forename: Fabien
authors.initials: F
authors.lastname: Dépis
authors.forename: Eric
authors.initials: E
authors.lastname: Hatterer
authors.forename: Romain
authors.initials: R
authors.lastname: Ballet
authors.forename: Bruno
authors.initials: B
authors.lastname: Daubeuf
authors.forename: Laura
authors.initials: L
authors.lastname: Cons
authors.forename: Sophie
authors.initials: S
authors.lastname: Glatt
authors.forename: Walter
authors.initials: W
authors.lastname: Reith
authors.forename: Marie
authors.initials: M
authors.lastname: Kosco-Vilbois
authors.forename: Yann
authors.initials: Y
authors.lastname: Dean
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D015202:Protein Engineering; D017452:Receptors, IgG / Q000276:immunology
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D017252:CD3 Complex; C115335:CD3E protein, human; D017452:Receptors, IgG
keywords: EAE; Monoclonal antibody; T cell activation; anti-CD3; oral antibody; pharmacodynamics; pharmacokinetics