Antibody-Cytokine Fusion Proteins: Harnessing the Combined Power of Cytokines and Antibodies for Cancer Therapy

Abstract

Advances in genetic engineering and expression systems have led to rapid progress in the development of tumor-specific antibodies fused to immunostimulators such as the cytokines interleukin-2 (IL-2), granulocyte/ macrophage colony-stimulating factor (GM-CSF), and interleukin-12 (IL-12). These “antibody-cytokine fusion proteins” combine the unique targeting ability of antibodies with the cytokine activity (1–3). The goal of this approach to cancer therapy is to concentrate the cytokine in the tumor microenvironment and in so doing directly enhance the tumoricidal effect of the antibody and/or enhance the host immune response against the tumor while limiting severe toxic side effects associated with the high dose of systemic cytokine administration. Multiple antibody-cytokine fusion proteins retaining both antibodyand cytokine-associated functions have been developed with different specificities targeting a broad variety of tumors. In animals bearing tumors, antibody-cytokine fusion proteins are able to localize at the tumor and to elicit a significant antitumor response that in some cases results in a complete elimination of the primary and metastatic tumors (4–7). These observations suggest that antibody-cytokine fusion proteins represent a new generation of effective immunotherapeutic reagents for the treatment of human cancer. The present review describes strategies for construction of antibody-cytokine fusion proteins, summarizes its advantages over other methods for cytokine delivery to the tumor microenvironment, and discusses the properties of several proteins with IgG genetically fused to the cytokines IL-2, GMCSF, or IL-12.