Immunotherapy for Infectious Diseases

208 Jacobson
Several groups have demonstrated the effectiveness of anti-HIV-1 monoclonal antibodies
in preventing infection after viral challenges in the hu-PBL-SCD mouse model.
A murine monoclonal antibody targeting the principal neutralizing determinant (PND)
of the V3 loop of HIV-1 IIIB (BAT123) and its mouse-human chimer (CGP 47 439),
given in a dose of 40 mg/kg, completely protected six mice each against subsequent
challenge with 10 MIDs of HIV-1 IIIB, a T-cell line (TCLA) strain. Five of the six animals
given control murine antibody became infected (112). BAT123 was found to be
100% protective against HIV LAI in doses as low as 1 mg/kg (113).
Another monoclonal antibody with neutralizing activity against the V3 loop of
HIV-1, 694/98-D, was found to provide 50% preexposure prophylaxis against HIV LAI
(a TCLA strain) when given at a dose of 1.32 mg/kg and 100% protection with a dose
of 40 mg/kg (114). The higher concentrations required for complete protection against
HIV LAI by MAb694/98-D compared with BAT123 may reflect in vitro neutralization
data. Fifty percent in vitro neutralization of HIV LAI against PBL target cells was
achieved with 0.6 �g/mL 694/98-D but only 0.09 �g/mL BAT123 (113,114), indicating
that BAT123 may be more potent than 694/98D against HIV LAI.
Studies of BAT123 were useful in correlating in vitro neutralization data with in vivo
anti-HIV protective activity. Complete protection of hu-PBL-SCID mice was achieved
with a serum concentration of 16 �g/mL of BAT123, close to the 15 �g/mL concentration
needed to achieve �99% in vitro neutralization. Only 43% protection was
obtained with a BAT123 concentration of 0.96 �g/mL, three times the 90% in vitro
neutralization concentration of 0.32 �g/mL (113). These data suggest that nearly 100%
in vitro neutralization concentrations of MAbs may be needed to provide complete protection
against HIV-1 infection in vivo (113). However, it should be noted that the dose
of HIV-1 that humans are exposed to is usually far less than the 10 MID 50s usually
used to challenge hu-PBL-SCID mice (115). In any event, these concentrations of
MAbs are achievable clinically, and certainly the doses employed are more feasible
than the 100 to >1000 mg/kg doses of HIVIG required to protect 50% of hu-PBL-SCID
mice from HIV-1 infection (116).
It is now known that primary isolates of HIV-1 are not as easily neutralized by antibodies
as are TCLA viruses (36,39). For example, BAT123 did not neutralize primary
isolates in vitro and failed to protect hu-PBL-SCID mice from infections with primary
isolates (113). IgG 1b12, a human monoclonal antibody directed against the CD4 binding
site (CD4bs) of gp120, has shown neutralizing activity against �75% of primary
HIV-1 isolates (40,48). Previously shown to protect hu-PBL-SCID mice against infection
with HIV-1 LAI, this antibody (117), when given in a dose of 50 mg/kg, completely
protected hu-PBL-SCID mice from challenge with the primary isolates HIV JR-CSF and
HIV AD6 (118). Once again, this dose provided serum concentrations corresponding to
levels giving 99% in vitro neutralization. Lower doses gave incomplete protection.
Similar results were seen for this antibody against the TCLA strain HIV-1 LAI. Serum
concentrations associated with 99% in vitro neutralization, provided by a dose of 10
mg/kg, were required for complete protection of hu-PBL-SCID mice. By contrast,
HIVIG showed no effect in protecting hu-PBL-SCID mice in these experiments.
Recently, a monoclonal antibody targeting the V3 loop of gp120 was found to protect
hu-PBL-SCID mice and Thy/Liv SCID-hu mice from infection with primary isolates
against which the antibody had in vitro neutralizing activity (119). HIV-induced