Anti-RSV F protein (Nirsevimab) (IVMB0549)

Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory tract infection and hospitalization in infants¹. RSV F protein is a type I integral membrane protein essential for viral membrane fusion that is highly conserved among isolates of RSV A and B subgroups². F protein has been investigated as a target for neutralizing antibodies, small molecular antiviral drug development, as a vaccine antigen, and as an antibody target for passive prophylaxis.

F protein is synthesized as an inactive, palmitoylated precursor (F₀) and is decorated with N-linked glycans². Three F₀ monomers form a trimer and become activated by a furin-like host protease as they pass through the Golgi. The protease cleaves twice, generating three polypeptides: F₂ and F₁, which are covalently linked, and pep27, an intervening peptide that dissociates after cleavage. When functional F protein trimer in the virion membrane is triggered, it undergoes a major conformational change from a prefusion to postfusion form. Approximately 25% of isolate specific variability for F protein is found within an antigenic site at the apex of the prefusion trimer (antigenic site Ø), composed of an α-helix from F₁ (aa 196–210) and a strand from F₂ (aa 62–69).

Nirsevimab is a long-acting, neutralizing recombinant human monoclonal antibody that binds the F₁ and F₂ subunits of F protein at a highly conserved epitope in antigenic site Ø and locks the RSV F protein in the prefusion conformation, blocking viral entry into the host cell^{1, 3, 4}. In vitro, nirsevimab binds to immobilized human FcγRs (FcγRI, FcγRIIA, FcγRIIB and FcγRIII)³. Protection from infection is thought to be dependent on neutralization activity rather than Fc-mediated effector function based on data from a cotton rat model of RSV infection³. Nirsevimab has been modified with a triple amino acid substitution (YTE) in the Fc region to extend the serum half-life³. Nirsevimab originates from the D25 antibody developed by AIMM Therapeutics and was jointly developed and commercialized by AstraZeneca and Sanofi for the prevention of RSV infection in neonates and infants.