In vitro potency, pharmacokinetic profiles, and pharmacological activity of optimized anti-IL-21R antibodies in a mouse model of lupus.

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.

Correlation of pharmacodynamic activity, pharmacokinetics, and anti-product antibody responses to anti-IL-21R antibody therapeutics following IV administration to cynomolgus monkeys.

Background: Anti-IL-21R antibodies are potential therapeutics for the treatment of autoimmune diseases. This study evaluated correlations between the pharmacodynamic (PD) activity, pharmacokinetics, and anti-product antibody responses of human anti-IL-21R antibodies Ab-01 and Ab-02 following IV administration to cynomolgus monkeys.

Methods: The PD assay was based on the ability of recombinant human IL-21 (rhuIL-21) to induce expression of the IL-2RA gene in cynomolgus monkey whole blood samples ex vivo.

Biodistribution of [125I]-labeled therapeutic proteins: application in protein drug development beyond oncology.

The majority of biodistribution studies of therapeutic proteins published to date focus on tumor-targeting agents. In this report we present a number of case studies that demonstrate the utility of biodistribution studies during preclinical development of biotherapeutics for non oncology indications, as well as provide a practical perspective on the methodology applied to these studies. For the commonly used classes of biologics (such as human monoclonal antibodies), biodistribution profiles may be compared to those of other therapeutics of the same class and compounds with unexpected off-target mediated uptake may be identified.

Pharmacokinetic and pharmacodynamic modeling of a humanized anti-IL-13 antibody in naive and Ascaris-challenged cynomolgus monkeys.

Purpose: Neutralization of IL-13 is an attractive approach for treatment of asthma. In this report, we developed a novel PK-PD model that described the relationship between the circulating concentrations of total IL-13 and a neutralizing anti-IL-13 antibody (Ab-02) in the model of acute airway inflammation induced by Ascaris challenge to cynomolgus monkeys, as well as in naive monkeys.

Methods: Cynomolgus monkeys were administered a single intravenous or subcutaneous dose of Ab-02.