In vitro potency,pharmacokinetic profiles and pharmacological activity of optimized anti-IL-21R antibodies in a mouse model of lupus |
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Authors: | Yulia Vugmeyster Heath Guay Pamela Szklut Ming D Qian Macy Jin Angela Widom Vikki Spaulding Frann Bennett Leslie Lowe Tatyana Andreyeva David Lowe Steven Lane George Thom Viia Valge-Archer Davinder Gill Deborah Young Laird Bloom |
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Institution: | 1.Department of Pharmacokinetics, Dynamics and Metabolism; Pfizer, Inc.; Andover, MA USA;2.Department of Inflammation and Immunology; Cambridge, MA USA;3.Department of Global Biotherapeutic Technologies; Pfizer, Inc.; Cambridge, MA USA;4.MedImmune, Inc.; Cambridge, UK |
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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 VL 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-Faslpr 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 (AUC0-∞) 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-Faslpr 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.Key words: affinity maturation, phage display, monoclonal antibody, autoimmunity, lupus, IL-21, IL-21R, pharmacokinetics, anti-product antibodies |
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