Immunotherapy for Infectious Diseases

78 Kunert and Katinger
whereas selected various escape mutants were found in the other two animals. There
is, however, some criticism with respect to the conclusion that these neutralizing antibodies
had a limited effect on the control of established HIV-1 infection in vivo. The
weak point in these experiments was that none of the single antibodies applied neutralized
the challenge virus potently in in vitro experiments.
Summarizing all the in vitro and animal model in vivo data available, one may conclude
that specifically selected combinations of passively administered monoclonal
antibodies have a high potential for the prevention of primary (mucosal) HIV-1 infection.
We even dare to express our view that passive immune therapy could replace the
current treatment of infants with inhibitors such as nucleoside analogs and nonnucleoside
reverse transcriptase inhibitors and protease inhibitors.
Considering all the facts known from animal and human trials, there are various
indications that antibodies might also contribute beneficially to the control of established
HIV-1 infection. Although immune intervention with passively administered
antibody combinations alone is probably not sufficient to control a full-blown viremia
combination with existing inhibitors such as highly active antiretroviral therapy
(HAART) would be compellingly logical. The current small-molecular inhibitors prevent
virus replication inside the infected cell, whereas non-ADE-neutralizing antibodies
prevent virus entry into the cell. Thus the therapeutic combination of antibodies
with existing inhibitors could combine complementary interventive mechanisms. Furthermore,
antibodies could additionally contribute to virus elimination by virus agglutination
and by sterilizing immune mechanisms via complement activation and ADCC.
One might also speculate that antibodies alone could control a low viremia once the
peak viral load is brought down to the limits of polymerase chain reaction (PCR)
detectability after combination treatment with the small-molecule inhibitors. If that was
the case, patients could afford periodic interruptions of the triple therapy in order to
recuperate from painful adverse effects while they are protected by well-tolerated antibodies.
Nobody knows the answer as long as there is no evidence from clinical trials.
Rheumatoid Arthritis
The progressive destruction of bone joints in rhematoid arthritis is mediated by activated
T-cells, macrophages, modified fibroblasts, and other inflammatory cells that
deliver potent inflammatory mediators, cytokines, and proteases. Emerging clinical
benefits are observed in antibody therapy directed toward the regulatory and effector
cells of the immune system and their cytokines. The clinical response seen with anti-
TNF antibodies (59) has confirmed the pivotal role of TNF in the process of disease
(60). Interventions directed towards T- and B-lymphocytes include antibodies against
CD3, CD4, CD5, CD7, CD25 (IL-2 receptor), and CD52 (CAMPATH-1), depleting
activated T-cells by binding to the cell surface (61). Clinical trials with nondepleting
anti-CD4 antibodies showed suppression of synovitis, but the state of improvement of
disease is unknown (62).
Cancer
Immunotherapy was and still is a central topic in tumor therapy. Cell surface antigens
of tumor cells are targets for therapeutic attachment with antibody fragments—
derivates and whole molecules. Most of the antibodies used today are directed against
surface molecules of tumor cells and serve as diagnostic agents as they are coupled