Motavizumab (MEDI-524, Numax) is a humanized IgG1 monoclonal antibody (mAb) developed by MedImmune Inc., a subsidiary of AstraZeneca. It is being investigated for the prevention of respiratory syncytial virus (RSV) infection in high-risk infants. In January 2008, a biologic license application for motavizumab was submitted to the US Food and Drug Administration (FDA) by MedImmune. The agency issued a complete response letter (CRL) in November 2008 asking for additional information. At that time, MedImmune was expected to respond to the CRL within the first half of 2009; the company did not foresee a need to conduct any additional trials. In June 2010, the FDA Antiviral Drugs Advisory Committee declined to endorse MedImmune's request for licensure of Motavizumab in a 14 to 3 decision. The members of that panel cited several reasons for the decision, and many were concerned that "we're not looking at a product that has evidence of superiority in terms of efficacy" when compared to the already available monoclonal antibody Palivizumab. In December 2010, AstraZeneca in a stock market statement stated that it would be writing down $445m after discontinuing a key development program for Motavizumab. The company stated that it would no longer develop Motavizumab for the prevention of RSV, and as a result was withdrawing its license application to the US Food and Drug Administration. It added that it would continue to develop Motavizumab for other treatments of RSV.
Motavizumab differs from palivizumab, its marketed predecessor, by 13 amino acid residues. Both mAbs target a highly conserved antigenic site A on the fusion (F) glycoprotein of RSV, but motavizumab has greater neutralizing activity compared to palivizumab. RSV F is a class I fusion glycoprotein that is synthesized as an inactive precursor (F0) that is processed by a furin-like protease at two sites to generate three polypeptides: the N-terminal fragment (F2), a 27-amino-acid glycopeptide (pep27) and the C-terminal fragment (F1). The mature, active protein exists as a trimer of F2-F1 heterodimers folded into a compact prefusion conformation. The process of membrane fusion begins once prefusion RSV F is triggered by an unknown mechanism to initiate a dramatic conformational change. This refolding can also occur spontaneously on virions and cell surfaces, and it can be stimulated with heat, indicating that prefusion RSV F is metastable. During the refolding, the hydrophobic fusion peptide at the N terminus of the F1 subunit pulls out from the central cavity of the prefusion trimer and inserts into the host-cell membrane. The resulting pre-hairpin intermediate then further refolds as the heptad repeats adjacent to the fusion peptide (HRA) associate with the heptad repeats adjacent to the viral transmembrane region (HRB), located near the C terminus of the F1 subunit. This association leads to the formation of an extremely stable six-helix bundle, which is characteristic of the RSV F postfusion conformation and brings the viral and host-cell membranes together. Inhibition of any of these steps during the fusion process may prevent entry and infection of the host cells and could thus serve as a target for therapeutic intervention. Motavizumab acts by binding the RSV F protein on the surface of the virus and blocking a critical step in the membrane fusion process.
Fig.1 Mechanism of action of Motavizumab