Development of a humanized monoclonal antibody (MEDI-493) with potent in vitro and in vivo activity against respiratory syncytial virus.
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 microg/mL. Further, MEDI-493 did not induce increased RSV infection or pathology in either a primary or a secondary challenge.
Johnson
S
S
MedImmune Inc., Gaithersburg, Maryland 20878, USA.
Oliver
C
C
Prince
G A
GA
Hemming
V G
VG
Pfarr
D S
DS
Wang
S C
SC
Dormitzer
M
M
O'Grady
J
J
Koenig
S
S
Tamura
J K
JK
Woods
R
R
Bansal
G
G
Couchenour
D
D
Tsao
E
E
Hall
W C
WC
Young
J F
JF
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D015707:HN Protein; D006801:Humans; D008969:Molecular Sequence Data; D018357:Respiratory Syncytial Virus Infections / Q000517:prevention & control*; D018113:Respiratory Syncytial Virus, Human / Q000276:immunology*; D016205:Sigmodontinae; D014759:Viral Envelope Proteins; D014764:Viral Proteins / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D015707:HN Protein; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C116204:attachment protein G