Immunotherapy for Infectious Diseases

74 Kunert and Katinger
persons of any age (17,18). Different preparations of hyperimmune sera are also available
against rabies for application after rabies exposure (19,20). Anti-thymocyte globulin
is extensively used in the treatment and prophylaxis of rejection episodes in renal
transplantations (21). Furthermore, these preparations are used in different bone
marrow recipients (22) and non-Hodgkin’s lymphomas (23) to reduce CD3-bearing
lymphocytes.
Other kinds of hyperimmune sera are the antitoxins and antitoxoids. With digoxin,
the antibody Fab fragments are prepared by immunizing sheep with digoxin coupled
to serum albumin as an adjuvant. Digoxin-immune Fab is then purified from sheep
blood and used in the neutralization of digitalis toxin (24,25). The protein was approved
by the FDA in 1986.
Problems Concerning Naturally Occurring Antibodies:
Non-ADE-Inducing Monoclonal Antibodies
Because of their polyclonality, it is expected that antisera have the entire set of effector
functions. Polyclonal antisera can prevent viral infections by different means. Binding
of antibody to virus-infected cells can trigger phagocytosis or ADCC or can induce
lysis via complement activation. However, a major question concerning the general
utility of polyclonal human hyperimmune sera was raised by the discovery of antibodydependent
enhancement (ADE) in various viral infections through the binding of the
Fc to Fc�RI� and Fc�RII� cells (26). Although the exact mechanisms of the ADE
phenomenon have not been determined, it is assumed that the virus/antibody complex
on the Fc receptor triggers signals that are relevant for increased cell infectivity. It is
also hypothesized that the virus/antibody complex is internalized via Fc/receptor interaction
and thus promotes increased infectivity. As found with different Flaviviriadeae
like dengue, yellow fever, Wesselsbron, West Nile, and tick-borne encephalitis viruses
ADE can modify cell susceptibility through virus-reactive antibodies (27,28).
Especially in asymptomatic HIV-1 patients, such antibodies with enhancing properties
on homologous and heterologous HIV-1 isolates have been found (29), and up to
95% of sera of HIV-infected persons revealed ADE (30). In other studies the phenomenon
of ADE could be assigned to distinct monoclonal antibodies (31,32). These findings
raise worries both for the establishment of a vaccine against HIV as well as for
the therapy of HIV-1 with HIVIG. Alternatively, these risks could be reduced by using
monoclonal antibodies as tools for mapping of non-ADE epitopes in vaccine design or
by using non-ADE-inducing monoclonal antibodies (or characterized cocktails) for
immunotherapy.
Monoclonal Antibodies in Therapy
Currently many “small synthetic molecules” are synthesized as drugs, which more
or less specifically inhibit the activity of targets such as enzymes or block ligand/
receptor-mediated pathways. This category of small-molecule drugs is often highly
efficient in the treatment of particular diseases and is relatively cheap to manufacture.
However, short half-lives as well as undesired and more or less severe adverse effects
are observed. More recently highly specific monoclonal antibodies have been established,
which will allow the pursuit of comparable therapeutic strategies with the
expectation of increased half-life and reduced toxicity. Some of these antibodies have