title: In vitro potency, pharmacokinetic profiles, and pharmacological activity of optimized anti-IL-21R antibodies in a mouse model of lupus.
abstract: Using phage display, we generated a panel of optimized neutralizing antibodies against the human and mouse receptors for interleukin 21 (IL-21), a cytokine that is implicated in the pathogenesis of many types of autoimmune disease. Two antibodies, Ab-01 and Ab-02, which differed by only four amino acids in V(L) CDR3, showed potent inhibition of human and mouse IL-21R in cell-based assays and were evaluated for their pharmacological and pharmacodynamic properties. Ab-01, but not Ab-02, significantly reduced a biomarker of disease (anti-dsDNA antibodies) and IgG deposits in the kidney in the MRL-Fas(lpr) mouse model of lupus, suggesting that anti-IL-21R antibodies may prove useful in the treatment of lupus. Ab-01 also had a consistently higher exposure (AUC(0-infinity)) than Ab-02 following a single dose in rodents or cynomolgus monkeys (2-3-fold or 4-7-fold, respectively). Our data demonstrate that small differences in CDR3 sequences of optimized antibodies can lead to profound differences in in vitro and in vivo properties, including differences in pharmacological activity and pharmacokinetic profiles. The lack of persistent activity of Ab-02 in the MRL-Fas(lpr) mouse lupus model may have been a consequence of faster elimination, reduced potency in blocking the effects of mouse IL-21R, and more potent/earlier onset of the anti-product response relative to Ab-01.
authors.affiliation: Department of Pharmacokinetics, Pfizer, Inc., Andover, MA, USA.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Vugmeyster
authors.forename: Heath
authors.initials: H
authors.lastname: Guay
authors.forename: Pamela
authors.initials: P
authors.lastname: Szklut
authors.forename: Ming D
authors.initials: MD
authors.lastname: Qian
authors.forename: Macy
authors.initials: M
authors.lastname: Jin
authors.forename: Angela
authors.initials: A
authors.lastname: Widom
authors.forename: Vikki
authors.initials: V
authors.lastname: Spaulding
authors.forename: Frann
authors.initials: F
authors.lastname: Bennett
authors.forename: Leslie
authors.initials: L
authors.lastname: Lowe
authors.forename: Tatyana
authors.initials: T
authors.lastname: Andreyeva
authors.forename: David
authors.initials: D
authors.lastname: Lowe
authors.forename: Steven
authors.initials: S
authors.lastname: Lane
authors.forename: George
authors.initials: G
authors.lastname: Thom
authors.forename: Viia
authors.initials: V
authors.lastname: Valge-Archer
authors.forename: Davinder
authors.initials: D
authors.lastname: Gill
authors.forename: Deborah
authors.initials: D
authors.lastname: Young
authors.forename: Laird
authors.initials: L
authors.lastname: Bloom
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage* / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics; D057134:Antibodies, Neutralizing / Q000008:administration & dosage* / Q000276:immunology; D002478:Cells, Cultured; D022801:Complementarity Determining Regions / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007378:Interleukins / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000628:therapy*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008815:Mice, Inbred Strains; D051381:Rats; D017207:Rats, Sprague-Dawley; D053655:Receptors, Interleukin-21 / Q000037:antagonists & inhibitors* / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D022801:Complementarity Determining Regions; D007378:Interleukins; D053655:Receptors, Interleukin-21; D000098546:Interleukin-21