Session: Slide Session: Respiratory Viruses and Hepatitis
Tuesday, October 28, 2008: 12:00 AM
Room: Room 145A
Background: Motavizumab (MZ) is an affinity-optimized anti-respiratory syncytial virus (RSV) monoclonal antibody (mAb) derived from palivizumab (Synagis®) (PZ). In vitro selection of mAb resistant mutants (MARMs) to PZ and MZ demonstrated amino acid (A.A.) changes at position 272 in the antigenic A site of RSV F protein where both MZ and PZ bind. PZ MARMs (K272M/Q/T/N) were only resistant to PZ, while the MZ MARM (K272E) was resistant to both antibodies. This study investigates whether these mutations appeared in 158 RSV-positive patients in a phase 3, randomized, double-blind, PZ-controlled study of MZ (MI-CP110). Methods: Genotypic analysis was carried out by sequencing the RSV F gene amplified directly from nasal specimen of RSV-positive subjects. The phenotype of the mutants was examined by performing microneutralization assays using recombinant RSV containing the identified mutations. Results: 5 RSV isolates contained an A.A. change at position 275 (S275L or S275F) and 3 isolates at position 272 (K272E or K272Q). The mutation K272Q was only identified in RSV from a PZ recipient, while the other three mutations were found in both treatment groups. The calculated A site mutation frequencies for RSV-positive MZ (4.7%) and PZ recipients (5.2%) were approximately equal. Phenotypic analysis indicated that S275L, S275F and K272Q mutations were associated with resistance to PZ but not to MZ, whereas the K272E mutation resulted in resistance to both mAbs. Conclusions: There were a small number of RSV-positive patients from the MZ (80 out of 3270) and PZ (100 out of 3246) treatment groups in MI-CP110. Among these RSV positive patients there was a low and comparable frequency of A site mutations (~5%) in F protein recovered from each treatment group. The clinical characteristics of the RSV events were consistent with the clinical presentation and time course expected for RSV.