Involvement of the complement system in the protection of mice from challenge with respiratory syncytial virus Long strain following passive immunization with monoclonal antibody 18A2B2

Abstract

Passive immunization of mice with 131 micrograms of the non-neutralizing monoclonal antibody (mAb) 18A2B2, directed against the A subgroup epitope of the G glycoprotein of respiratory syncytial virus Long strain (RSV), confers protection against viral i.n. challenge. The role of the Fc fragment of this antibody as well as the involvement of antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytolysis towards protection was evaluated in vivo. Passive immunization with the Fab fragment alone (618-907 micrograms mouse-1) was unable to confer protection in mice. Furthermore, we passively immunized with the mAb 18A2B2 SCID beige mice, which are deficient in natural killer (NK) cell activity, to ascertain the role of NK cells in the protective mechanism. These mice were free of virus 5 days following viral challenge, indicating that NK cells do not contribute significantly towards the protective action of this antibody. Moreover, passively immunized BALB/c mice decomplemented with 8-10 U of cobra venom factor (CoVF) and DBA/2J mice (C5 deficient) were only partially protected. These findings suggest that in mice the alternative and classical pathways of the complement system are involved in the passive protection mechanism conferred by the non-neutralizing mAb 18A2B2. To our knowledge, it is the first description of a protective mechanism in mice that involves a non-neutralizing antibody and the complement system.

Treatment with respiratory syncytial virus G glycoprotein monoclonal antibody or F(ab′)2 components mediates reduced pulmonary inflammation in mice

“…Two days after mAb 131-2G treatment, the viral load in mice treated with intact mAb was significantly (P,0.048) reduced compared with lung titres in F(ab9) 2 -treated mice which showed no significant reduction compared with nIgtreated mice. The ability of this non-neutralizing antibody to prevent virus replication in vivo is consistent with earlier observations and reports using other non-neutralizing RSV G protein antibodies (Corbeil et al, 1996;PlotnickyGilquin et al, 1999;Mekseepralard et al, 2006). The results suggest that mAb 131-2G may mediate virus clearance through an ADCC mechanism.…”

“…Others have demonstrated that non-neutralizing anti-RSV G protein mAbs are sufficient to protect against RSV infection in mouse models (Corbeil et al, 1996;Plotnicky-Gilquin et al, 1999;Mekseepralard et al, 2006). For example, it was reported that passive administration of a non-neutralizing mAb (18A2B2) against the central conserved region of RSV G protein subgroup A protected mice from RSV infection (Corbeil et al 1996).…”

“…Others have demonstrated that non-neutralizing anti-RSV G protein mAbs are sufficient to protect against RSV infection in mouse models (Corbeil et al, 1996;Plotnicky-Gilquin et al, 1999;Mekseepralard et al, 2006). For example, it was reported that passive administration of a non-neutralizing mAb (18A2B2) against the central conserved region of RSV G protein subgroup A protected mice from RSV infection (Corbeil et al 1996). In these previous studies, treatment with the same mAb in complement-deficient mice or treatment with mAb F(ab9) 2 fragments did not confer complete protection, suggesting that protection by the intact mAb involved both Fc-dependent pathways and the complement system (Corbeil et al, 1996).…”

“…For example, it was reported that passive administration of a non-neutralizing mAb (18A2B2) against the central conserved region of RSV G protein subgroup A protected mice from RSV infection (Corbeil et al 1996). In these previous studies, treatment with the same mAb in complement-deficient mice or treatment with mAb F(ab9) 2 fragments did not confer complete protection, suggesting that protection by the intact mAb involved both Fc-dependent pathways and the complement system (Corbeil et al, 1996). Other studies investigating a different subgroup A-specific anti-RSV G mAb (1C2) that recognized a similar region on the G protein, and a related mouse-human chimeric mAb (c1 1C2), showed a level of protection against RSV infection when these antibodies were administered prophylactically to BALB/c mice (Mekseepralard et al 2006).…”

Virus-Neutralizing Activity Mediated by the Fab Fragment of a Hemagglutinin-Specific Antibody Is Sufficient for the Resolution of Influenza Virus Infection in SCID Mice

“…However, the protective activity of monovalent Ab fragments has been tested against other viruses, including Venezuelan equine encephalitis virus (25), respiratory syncytial virus (RSV) (6, 9, 10), murine hepatitis virus (20), hantavirus (23), herpes simplex virus (52), and vesicular stomatitis virus (19). These studies showed that Fab fragments from VN-negative Abs were ineffective in vivo (6,9), which is consistent with the notion that Fab contributes to the control of infection mainly, if not exclusively, by VN activity. In addition, they showed that Fab or single-chain Fv (scFv) fragments with VN activity were usually ineffective when administered systemically.…”