Immunotherapy for Infectious Diseases

Production of Igs and MAbs Targeting Infectious Diseases 79
with radioisotopes such as 111 In or 99 Tc. Two MAbs have been applied in therapeutic
use. Anti-HER2 MAbs are directed against a member of the human growth factor
receptor family and inhibits the expansion of breast cancer cells in tumors with HER2
overexpression (63). Another MAb with therapeutic significance is directed against the
cell surface protein CD20 (64). Patients with non-Hodgkin’s lymphoma and chronic
lymphocyte leukemia are thus depleted of lymphocytes and platelets (65). A promising
set of strategies employs radioisotopes or toxins that are attached to the antibodies
as a means of targeting cytotoxicity (“the magic bullet” concept).
Immunosuppression and Transplation
The MAb OKT3 was pioneered with the idea of using antibodies in the field of
immunosuppression and organ transplantation. The murine monoclonal antibody OKT3
(66) has been used since 1986 to improve graft survival and also to reduce the dose of
toxic drugs such as cyclosporin. The main disadvantage of this anti-CD3 antibody is its
murine origin and its significant immune response (67). Another target for immunosuppression
in organ transplantation is CD25, the IL-2 receptor (68). Such antibodies are
directed against activated T-cells and reduce acute rejection episodes in combination with
cyclosporin and steroids (69). Anti-TNF antibodies have also shown some encouraging
activities (70,71) in the suppression of immune response after organ transplantations. The
main drawback of immunosuppression strategies is the risk of unwanted infections after
broad immunosuppression and massive release of proinflammatory cytokines (72).
Cardiovascular diseases
Disorders of the cardiovascular system are often related to platelet aggregation or
coagulation, causing arterial reocclusion or venous thrombosis. An anti-integrin MAb
received marketing approval in 1994 and is directed against adhesion molecules
involved in the final common pathway for platelet aggregation. The antibody Fab fragment
is a chimeric human/mouse molecule and binds to the integrin GPIIb/IIIa (73,74).
Other antibodies reactive in cardiovascular system diseases are directed against von
Willebrand factor (75) and tissue factor.
APPROACHES AND TECHNIQUES
FOR ESTABLISHING HUMAN MONOCLONAL ANTIBODIES
Today a broad variety of techniques to establish monoclonal antibodies are available.
Through the use of cell immortalization and cell culture technologies, it was possible
to isolate and grow antibody-expressing B-lymphocytes of rodent as well as
human origin. Molecular engineering made it possible to express antibodies and their
derivates in various host systems. Nevertheless, most MAbs used today were initially
established through the humoral immune system from vaccinated or naturally infected
mammals, in combination with B-cell immortalization techniques. Once the functions
of those antibodies were established, the encoding genes were accessible for manipulation
and expression in a host system of choice.
Immortalization of Human B-lymphocytes: Hybridoma Technology
The human immune system is a preferred source of antibody-producing B-lymphocytes.
Vaccinated persons, infected, and/or reconvalescent patients represent an ideal source of
antigen-primed B-lymphocytes either as a gene donor or for direct immortalization.