Immunotherapy for Infectious Diseases

Passive Immunotherapy for HIV Infection 203
anism of ADCC, cell-mediated cytotoxicity (CMC), has been described in which natural
killer (NK) cells with anti-HIV antibody bound to their Fc receptors (CD16) target
HIV-infected cells coated with HIV envelope antigen (gp120) (76). Lin et al. (77)
showed that gp120-specific CMC could be augumented by interleukin-2 (IL-2), IL-12,
and IL-15 and could be augmented further by combining IL-2 and IL-15. The addition
of HIVIG also enhanced CMC (77). The anti-HIV monoclonal antibodies 2G12 and
F105 have demonstrated ADCC activity (46,78).
Bispecific Antibodies
Another approach to enhance and broaden the activities of antibodies and effector
cells is the creation of bispecific antibodies (BsAbs) (79). One type of BsAb combines
two monoclonal antibodies with neutralizing activity against different HIV epitopes.
Using the hybridoma cell fusion technique, Gorny et al. (79) combined MAbs targeting
conserved epitopes of V3 with MAbs against the CD4 binding domain. The BsAbs
created had synergistic anti-HIV activity when tested against the HIV-1IIIB laboratoryadapted
strain (79). These antibodies presumably would have all the advantages of
using combinations of single MAbs.
Another type of BsAb combines anti-HIV and anti-effector cell specificities to mediate
ADCC against HIV-infected cells (79). Antibodies against Fc�RI, a signaling receptor
on monocytes, macrophages, and activated neutrophils, were combined with MAbs
against HIV-1 envelope epitopes. The resultant BsAbs were shown to mediate lysis of
gp160-transfected CEM cells by Fc�RI-expressing U-937 cells, a monocytoid cell line
(79). A BsAb containing anti-V3 and anti-Fc�RI components had the highest activity.
Importantly, these antibodies did not mediate antibody-dependent enhancement of HIV
infection.
Other Mechanisms of Anti-HIV Antibody Activity
There are other mechanisms by which antibodies could control HIV infection (Table
2). One is through complement-mediated lysis of free virus or viral-infected cells
(80,81). V3 peptides inhibit complement-mediated virolysis by the serum of HIVinfected
persons (82), and MAb 694/98D, an anti-V3 antibody has been shown to be
complement-activating (83). Antibody binding of gp120 expressed on infected cell surfaces
could inhibit fusion of cells, syncytia formation, and cell-to-cell spread to virus
(84). In addition, antibodies could serve to clear immunosuppressive HIV proteins,
such as gp120. Soluble gp120 is known to impair CD4 lymphocyte function and to promote
cell-mediated lysis of uninfected CD4 cells (85–89). Finally, neutralizing antibodies
have also been found to inhibit the infection of dendritic cells and the subsequent
transmission to T cells, thus potentially interfering with the early events around mucosal
HIV transmission (90).
However, some antibodies could have deleterious effects on the course of HIV infection.
Anti-gp120 antibodies could mediate lysis of uninfected CD4 cells with free
gp120 shed by the virus bound to its surface (85). In addition, some antibodies that
bind virus could enhance HIV infection of cells via binding of antibody-HIV complexes
to Fc or complement receptors on mononuclear phagocytes or dendritic cells
(91,92).