Immunotherapy for Infectious Diseases

Passive Immunotherapy for HIV Infection 209
atrophy of the thymic transplants in the SCID-hu mice was prevented by the prior
administration of antibody.
It should be noted that in an acute human to mouse xenograft model in which
donated human monocytes and lymphocytes are in an activated state, monoclonal antibodies
with demonstrated in vitro neutralizing activity against primary isolates failed
to provide in vivo protection against infection (120). Since activated cells are more supportive
of HIV infection, this animal model is a more difficult one for neutralizing antibodies
to demonstrate activity.
Postexposure Studies in SCID Mice
To study the potential role of antibodies in postexposure protection against HIV infection,
the antibodies can be administered at several time points after the hu-PBL-SCID mice are
challenged with virus. Anti-V3, anti-CD4-BS, anti-gp41, and other antibodies affect the
virus-host cell interaction subsequent to gp120-CD4 binding (121,122). Thus, they might be
effective at preventing the establishment of infection even after virus challenge. The anti-V3
BAT123 antibody was found to protect hu-PBL-SCID mice from infection when given up
to 4 hours after HIV-1LAI challenge (115). It was 62% effective when given 5 hours after
challenge and 33% effective when given 6 hours or more after challenge. Anti-CD4-BS
IgGb12 provided complete protection against laboratory-adapted (HIV-1LAI) and primary
(HIV-1JR-CSF and HIV-1AD6) isolates when given within 6 hours of HIV-1 challenge and partial
protection when given at 8 and 24 hours after challenge (118). When viral breakthrough
occurred, both BAT123 and IgGb12 had no effect on subsequent viral burden. By contrast,
HIVIG had to be given within 1 hour of viral challenge to be effective (116). The anti-V3
antibody 694/98-D achieved 100% protection when given 15 minutes after HIVLAI challenge
and was 50% effective when given 1 hour after challenge (114). The anti-CD4 B4 antibody
protected mice for up to 4 hours after challenge with a primary HIV-1 isolate (72).
Role of Antibody-Dependent Cellular Cytotoxicity and Complement
Aside from potency, monoclonal antibodies may differ in their ability to effect
ADCC and complement-mediated antiviral effects. BAT123 has been shown to mediate
ADCC (115). Replacing the murine Fc domain of BAT123 with a human IgG1 Fc
domain eliminated the postexposure prophylactic effectiveness of this antibody in the hu-
PBL-SCID mouse model (123). In addition, giving the mice cobra venom factor to inactivate
serum complement activity also interfered with the postexposure prophylactic
effect of BAT123 (123). Thus, the complement system is important for the anti-HIV
activity of BAT123 and probably other antibodies. On the other hand, providing complement
did not change 694/98-D’s activity in providing postexposure prophylaxis (114).
Escape Mutation
In an important study, HIV-1LAI virus isolated from one hu-PBL-SCID mouse 3
weeks after receiving antibody 694/98-D as preexposure prophylaxis was found to be
resistant to neutralization by 694/98-D (114). Sequence analysis of the V3 region of
this virus demonstrated amino acid changes in the epitope recognized by 694/98-D and
in one amino acid nearby. Thus, mutation leading to escape from neutralization is a
risk of therapy with one monoclonal antibody and supports the need for studying combinations
of antibodies.