Protection of mice against Human respiratory syncytial virus by wild-type and aglycosyl mouse-human chimaeric IgG antibodies to subgroup-conserved epitopes on the G glycoprotein.
Monoclonal antibodies (mAbs) to conserved epitopes on the G glycoprotein of human respiratory syncytial virus (HRSV) subgroup A fail to neutralize the virus in cell culture in the absence of complement, but are protective in rodent models of infection. They may have potential as prophylactic agents in human infants. In order to investigate the role of Fc-dependent pathways in protection by one such antibody, 1C2, the V(H) and V(L) genes were isolated by RT-PCR and assembled with human kappa light-chain and human gamma1 heavy-chain constant-region genes to form two mouse-human chimaeras, which were expressed in NS0 cells. One of the chimaeras carried a wild-type gamma1 chain, whilst the other had an aglycosyl mutation in the C(H)2 domain rendering the antibody defective in complement activation and FcgammaR binding. Whilst both chimaeric antibodies exhibited similar avidity for HRSV in ELISA, only the fully glycosylated wild type was capable of neutralizing the virus in the presence of complement. In mice passively immunized with either murine or wild-type gamma1 chimaeric antibody, no virus could be recovered from the lungs 4 days after intranasal inoculation of HRSV. In mice immunized with the aglycosyl gamma1 chimaera, however, virus was present in the lungs following challenge, although virus titres were significantly reduced compared with controls (P < 0.005). These results indicate that the protective effect of this antibody is mediated by both Fc-dependent and Fc-independent pathways.
Mekseepralard
C
C
The Schools of Clinical Medical Sciences and Cell and Molecular Biosciences, The University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK.
Toms
G L
GL
The Schools of Clinical Medical Sciences and Cell and Molecular Biosciences, The University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK.
Routledge
E G
EG
The Schools of Clinical Medical Sciences and Cell and Molecular Biosciences, The University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology*; D000914:Antibodies, Viral / Q000008:administration & dosage / Q000096:biosynthesis / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D006801:Humans; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000096:biosynthesis / Q000276:immunology*; D007275:Injections, Intravenous; D051379:Mice; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D018357:Respiratory Syncytial Virus Infections / Q000517:prevention & control*; D018113:Respiratory Syncytial Virus, Human / Q000276:immunology*; D014760:Viral Fusion Proteins / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D000939:Epitopes; C502275:G glycoprotein, Respiratory syncytial virus; D007074:Immunoglobulin G; D014760:Viral Fusion Proteins