Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

16
Immunocytokines: Versatile Molecules for Biotherapy
of Malignant Disease
Holger N. Lode, Rong Xiang, Jçrgen C. Becker, Andreas G. Niethammer,
F. James Primus, Stephen D. Gillies and Ralph A. Reisfeld
16.1
Introduction
Sixteen years after the discovery of antibodies by Emil von Behring in 1890, Paul Ehrlich
proposed their use as ªmagic bullets and poisoned arrowsº to specifically target
toxic substances to pathogenic targets [1]. However, it required almost another century
before such antibody-based therapies were applied to the management of residual
disease that remains a major problem in the treatment of cancer. This strategy
was made possible by the discovery of monoclonal antibodies (mAbs) directed
against well-characterized antigens by Kæhler and Milstein in 1975 [2]. It was further
accelerated and extended by the subsequent introduction of DNA technologies and
their rapidly developing advances which facilitated the development of an ever-increasing
array of bioengineered antibodies and their fragments during the last 25
years. This chapter deals with one such product of bioengineered antibodies, recombinant
antibody±cytokine fusion proteins, and focuses entirely on data obtained with
these immunocytokines in preclinical studies in the authors' laboratories with emphasis
on evaluating their efficacy in eradicating established tumors and metastases
in syngeneic mice. In addition, we will describe extended applications of immunocytokines
in combination with gene therapies, anti-angiogenesis treatment modalities
and DNA-based cancer vaccines to prevent or eradicate tumor metastases.
16.1.1
Immunocytokines
Cancer Immune Therapie: Current and Future Strategies
Edited by G. Stuhler and P. Walden
Copyright # 2002 Wiley-VCH Verlag GmbH & Co. KGaA
ISBNs: 3-527-30441-X (Hardback); 3-527-60079-5
(Electronic)
Recombinant antibody±cytokine fusion proteins are immunocytokines designed to
achieve sufficient concentrations in the tumor microenvironment to effectively stimulate
a cell-mediated immune response against tumors. This approach differs from passive
immunotherapy by antibodies directed against tumor-associated antigens (TAAs),
which utilizes the natural effector mechanisms of antibodies to destroy tumor cells. A
key feature of immunocytokines is to provide a tool for active cancer immunotherapy
by increasing the cytokine concentration in the tumor microenvironment, thereby po-
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