title: Pharmacogenomics and translational simulations to bridge indications for an anti-interferon-α receptor antibody.
abstract: A type I interferon (IFN) gene signature shared by systemic lupus erythematous (SLE) and systemic sclerosis (SSc) was used to evaluate an anti-type I IFN-α receptor (IFN-αR) monoclonal antibody, MEDI-546, in a phase I trial in SSc. MEDI-546 suppressed IFN signature in blood and skin of SSc patients in a dose-dependent manner. To bridge clinical indications to SLE, we developed a model incorporating (i) pharmacokinetics (PK) and pharmacodynamics (PD) in SSc patients, (ii) internalization kinetics of MEDI-546/IFN-αR complex, and (iii) the different IFN signatures between SSc and SLE. Simulations predicted that i.v. administration of MEDI-546 at 300- or 1,000-mg monthly doses could suppress IFN signature in blood to levels of healthy subjects in 53 and 68% of SLE patients, respectively. An innovative approach utilizing a novel biomarker characterized the PD of MEDI-546 by modeling and simulation and allowed rapid progression of MEDI-546 from a phase I study in SSc to a randomized, multiple-dose phase II trial.
authors.affiliation: Department of Translational Sciences, MedImmune, LLC, Gaithersburg, Maryland, USA.
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.forename: B W
authors.initials: BW
authors.lastname: Higgs
authors.forename: L
authors.initials: L
authors.lastname: Chang
authors.forename: I
authors.initials: I
authors.lastname: Vainshtein
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.forename: K
authors.initials: K
authors.lastname: Streicher
authors.forename: M
authors.initials: M
authors.lastname: Liang
authors.forename: W I
authors.initials: WI
authors.lastname: White
authors.forename: S
authors.initials: S
authors.lastname: Yoo
authors.forename: L
authors.initials: L
authors.lastname: Richman
authors.forename: B
authors.initials: B
authors.lastname: Jallal
authors.forename: L
authors.initials: L
authors.lastname: Roskos
authors.forename: Y
authors.initials: Y
authors.lastname: Yao
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D017322:Clinical Trials, Phase II as Topic; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010597:Pharmacogenetics; D053633:Receptor, Interferon alpha-beta / Q000276:immunology* / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D012867:Skin / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D016898:Interferon-alpha; D053633:Receptor, Interferon alpha-beta; C582345:anifrolumab