Potent high-affinity antibodies for treatment and prophylaxis of respiratory syncytial virus derived from B cells of infected patients.
Native human Abs represent attractive drug candidates; however, the low frequency of B cells expressing high-quality Abs has posed a barrier to discovery. Using a novel single-cell phenotyping technology, we have overcome this barrier to discover human Abs targeting the conserved but poorly immunogenic central motif of respiratory syncytial virus (RSV) G protein. For the entire cohort of 24 subjects with recent RSV infection, B cells producing Abs meeting these stringent specificity criteria were rare, <10 per million. Several of the newly cloned Abs bind to the RSV G protein central conserved motif with very high affinity (K(d) 1-24 pM). Two of the Abs were characterized in detail and compared with palivizumab, a humanized mAb against the RSV F protein. Relative to palivizumab, the anti-G Abs showed improved viral neutralization potency in vitro and enhanced reduction of infectious virus in a prophylaxis mouse model. Furthermore, in a mouse model for postinfection treatment, both anti-G Abs were significantly more effective than palivizumab at reducing viral load. The combination of activity in mouse models for both prophylaxis and treatment makes these high-affinity human-derived Abs promising candidates for human clinical testing.
Trellis Bioscience, South San Francisco, CA 94080, USA.
Ellen J
EJ
Collarini
F Eun-Hyung
FE
Lee
Orit
O
Foord
Minha
M
Park
Gizette
G
Sperinde
Hai
H
Wu
William D
WD
Harriman
Stephen F
SF
Carroll
Stote L
SL
Ellsworth
Larry J
LJ
Anderson
Ralph A
RA
Tripp
Edward E
EE
Walsh
Bruce A
BA
Keyt
Lawrence M
LM
Kauvar
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000914:Antibodies, Viral / Q000276:immunology / Q000627:therapeutic use*; D000915:Antibody Affinity / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000821:virology; D002460:Cell Line; D006801:Humans; D051379:Mice; D009500:Neutralization Tests; D000069455:Palivizumab; D011994:Recombinant Proteins / Q000276:immunology; D018357:Respiratory Syncytial Virus Infections / Q000517:prevention & control / Q000628:therapy*; D018113:Respiratory Syncytial Virus, Human / Q000276:immunology*; D014162:Transfection; D014760:Viral Fusion Proteins / Q000276:immunology*; D019562:Viral Load / Q000187:drug effects / Q000276:immunology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000914:Antibodies, Viral; D000956:Antigens, Viral; C502275:G glycoprotein, Respiratory syncytial virus; D011994:Recombinant Proteins; D014760:Viral Fusion Proteins; D000069455:Palivizumab