Immunotherapy for Infectious Diseases

Production of Igs and MAbs Targeting Infectious Diseases 75
been successfully applied in human clinical trials and have received FDA marketing
approval. In addition to their binding specificity, antibodies are able to confer important
effector functions. In the following section we describe some cases in which experience
in the use of therapeutic antibodies has been compiled.
Sepsis Syndrome
Sepsis syndrome, or systemic inflammatory response syndrome, is a clinical feature
that occurs with serious systemic infections from Gram-negative bacteria or viruses.
The stereotypical picture of septic shock occurs after trauma, hemorrhage, pancreatitis,
and immune-mediated tissue injury. Many of the features of sepsis can be mimicked
by certain cytokines, such as tumor necrosis factor (TNF) or IL-1. These individual
cytokines or cellular mediators have been the targets in clinical trials. A range of different
antibodies and antibody-based products has been tested that neutralize TNF (33)
and prevent mortality in animal models of sepsis. Other interesting antibodies are
directed against IL-8 (34), complement proteins, intercellular adhesion molecule
(ICAM-1) (35), and E-selectin (36), which also cause neutrophil-mediated damage.
Another strategy is to block the cause of sepsis, namely, the effects of endotoxins
of Gram-negative bacteria. Unfortunately, initial trials have not demonstrated a single
antibody that was able to prevent or cure sepsis (37–39).
Infectious Diseases
A successful strategy for defending different viral infections requires the establishment
of antibodies against protective epitopes. The identification of such epitopes is
the most important step in efficient antibody development. The envelope glycoproteins
of bacteria and viruses present such immunoreactive structures. The characterization of
corresponding antibodies has confirmed their role for humoral protection. Usually, the
most efficient neutralizing and protective antibodies are generated by the mammalian
humoral immune system upon natural infection, probably because during primary
infection complex oligomeric antigenic structures are presented in their native form.
However, the humoral immune defense of the infected host can be misled by its own
defensive activity. The destruction of the infective pathogen may result in the circulation
of antigenic debris that in no way represents the antigenic pressure of the original
infection. In such a case the humoral immune response is induced to produce antibodies
against epitopes that are irrelevant or even unfavorable. Mutation frequency of the
infective agent is another mechanism for evading the humoral immune response. Infectious
agents such as RNA viruses display the highest mutational frequencies. Monoclonal
antibodies have been developed against a variety of infections including HVZ,
CMV, herpes simplex virus, papillomavirus, hepatitis B virus, and HIV. Up to now the
only one used for human therapy is a monoclonal antibody against RSV envelope glycoprotein
(40,41).
Antibodies Against HIV
The humoral immune response to HIV-1 has been intensively studied. Considerable
understanding of many details of the viral infective routes via receptor- and coreceptormediated
mechanisms has been established. However, we are still far from a complete
understanding of the role of antibodies in the prevention of primary infection and their
role in the control of viremia during the chronic phases of infection. There is evidence