A recombinant single-chain antibody interleukin-2 fusion protein

Abstract

SummaryRecombinant interleukin-2 (rIL-2) therapy has been shown to be of value in the treatment of some cases of melanoma and renal cell carinoma. However its use can be limited by severe systemic toxicity. Targeting rIL-2 to the tumour should improve the anti-tumour immune response and decrease the systemic toxicity. With this aim we have employed recombinant DNA techniques to construct a single chain antibody interleukin-2 fusion protein (SCA-IL-2).The protein used in this model system comprises the variable domains of the anti-lysozyme antibody D1.3 fused to human IL-2. It has been expressed by secretion from Escherichia coli and the purified product possesses antigen binding specificity and retains the immunostimulatory activities of rIL-2.This approach can be taken to generate SCA-IL-2 proteins that bind to appropriate cellular antigens. In vivo administration of a tumour binding SCA-IL-2 should result in a localised high concentration of IL-2 in tumour tissues, maximising the anti-tumour immune response, whilst keeping systemic side effects to a minimum.

Expression, engineering and characterization of the tumor-targeting heterodimeric immunocytokine F8-IL12

“…To overcome these problems, the use of 'immunocytokines' (i.e. cytokines fused to antibodies or antibody fragments) has been proposed, with the aim to concentrate the immune-system stimulating activity at the site of disease while sparing normal tissues (Savage et al, 1993;Reisfeld et al, 1997;Dela Cruz et al, 2004;Neri and Bicknell, 2005;Schrama et al, 2006).…”

Delivering cytokines at tumor site: The immunocytokine-conjugated anti-EDB-fibronectin antibody case

“…Although IL2 has no direct cytotoxic effects on cancer cells, it can induce tumor regression by means of its ability to stimulate a potent cell-mediated response in vivo (Rosenberg 2000). To overcome systemic toxicity, but at the same time to deliver therapeutically efficacious amounts of IL2 to neoplastic tissue, a number of preclinical experiments on murine tumor models have been carried out using fusion proteins composed of IL2 and antibodies with different specificities (Becker et al 1996;Fell et al 1991;Harvill et al 1996;Lode et al 1998;Melani et al 1998;Sabzevari et al 1994;Savage et al 1993;Xu et al 2000). Although these observations clearly proved the concept that the targeted delivery of IL2 enhances its therapeutic efficacy, the experiments were carried out using artificially overexpressed tumor cell surface antigens.…”

Antibody-cytokine fusion proteins: A novel class of biopharmaceuticals for the therapy of cancer and of chronic inflammation

“…The first immunocytokines based on IL2 were developed more than two decades ago, featuring either full immunoglobulins or antibodies in scFv format [48,84,85]. A potent anti-cancer activity has been reported for animal models of murine colon carcinoma, human metastatic melanoma, prostate carcinoma and neuroblastoma, using antibodies specific to an epithelial cell adhesion protein (EpCAM G733-2) and the ganglioside GD2 [8,[86][87][88].…”