Development of a Humanized Monoclonal Antibody (MEDI‐493) with Potent In Vitro and In Vivo Activity against Respiratory Syncytial Virus

TLDR

Neutralizing polyclonal antibodies against RSV are effective prophylaxis when given intravenously to high‑risk infants. The study aims to generate a humanized monoclonal antibody, MEDI‑493, targeting a conserved neutralizing epitope on the RSV F protein. MEDI‑493 was engineered to recognize a conserved epitope on the RSV F glycoprotein. MEDI‑493 exhibited high affinity comparable or superior to a chimeric derivative, was markedly more potent in plaque‑reduction, microneutralization, and fusion‑inhibition assays, neutralized 57 RSV A/B isolates, and reduced lung RSV titers by 99 % in cotton rats at 2.5 mg/kg without enhancing infection or pathology.

Abstract

Neutralizing polyclonal antibody to respiratory syncytial virus (RSV) has been shown to be an effective prophylactic agent when administered intravenously in high-risk infants. This study describes the generation of a humanized monoclonal antibody, MEDI-493, that recognizes a conserved neutralizing epitope on the F glycoprotein of RSV. The affinity of MEDI-493 was found to be equal to or slightly better than an isotype-matched chimeric derivative of the parent antibody. In plaque reduction, microneutralization, and fusion-inhibition assays, MEDI-493 was significantly more potent than the polyclonal preparation. Broad neutralization of a panel of 57 clinical isolates of the RSV A and B subtypes was demonstrated. Pretreatment of cotton rats with MEDI-493 resulted in 99% reduction of lung RSV titers at a dose of 2.5 mg/kg, corresponding to a serum concentration of 25–30 µg/mL. Further, MEDI-493 did not induce increased RSV infection or pathology in either a primary or a secondary challenge.