Generation and preclinical assessment of depemokimab, an enhanced IL-5 antagonist monoclonal antibody

<h2>Abstract</h2> This study describes the affinity maturation, molecular engineering, and preclinical assessment of depemokimab, an enhanced anti-interleukin-5 antagonist antibody. The molecular design objective for depemokimab was to generate a therapeutic antibody enabling a less frequent dosing regimen of once every 6 months compared with every 4 weeks for mepolizumab. Mepolizumab is a marketed monoclonal antibody used as an add-on prescription maintenance treatment for patients with severe asthma with an eosinophilic phenotype and other eosinophilic-associated disorders. A complementarity-determining region restricted affinity maturation strategy was used where affinity improved interleukin-5 binding antibody variants were subject to affinity driven selective pressure and identified using the Adimab yeast-based platform. Improved complementarity-determining region variants were combined with serum half-life extending amino acid mutations introduced into the fragment crystallizable region of the antibody. When compared with mepolizumab, depemokimab demonstrated improved <i>in vitro</i> interleukin-5 neutralization in a TF-1 (human erythroleukemia) functional cell assay. <i>In vivo</i>, depemokimab displayed significantly extended pharmacokinetic performance and pharmacodynamic duration determined via eosinophil suppression in cynomolgus monkey (<i>Macaca fascicularis</i>). These data provide compelling evidence that a less frequent dosing regimen for depemokimab in humans is possible and supported the advancement of depemokimab into a Phase I study in patients with asthma.