Immunotherapeutic effect of an interleukin-2 immunoconjugate in animal model

Abstract

Recombinant antibody-cytokine fusion proteins are immunocytokines that deliver high cytokine concentrations in the targeted tumor microenvironment and thereby effectively stimulate cellular immune responses against human malignancies. Protoon-cogene HER-2/neu is overexpressed in some human breast, ovarian, prostate and lung cancers and associated with poor prognosis. A novel immunocytokine consisting of a recombinant human interleukin-2 (rhIL-2) and a recombinant humanized single chain antibody that combined the VH and VL portions of a murine monoclonal antibody (520C9) specific for human HER-2/neu positive tumors has been developed. The fusion protein H520C9sFv-rhIL-2 in combination with human peripheral blood mononuclear cells effectively inhibited growth and dissemination of subcutaneous xenograft and lung metastases of human HER-2/neu positive ovarian carcinoma in severe combined immunodeficient mice. In addition, histological staining and immunohistochemical analysis of lung metastases in the treatment group of SCID mice with the H520C9sFv-rhIL-2 and human PBM cells demonstrated significant suppression of metastatic tumor growth. A dose dependent response was also demonstrated by the effective inhibition of lung metastases at a dose level of 6 ug H520C9sFv-rhJL-2 instead of 3 ug H520C9sFv-rhIL-2 per injection with 2 x 105 human PBM cells. Such results demonstrated that immunocytokine-directed inter1eukin-2 therapy to tumors sites could be effective in an adjuvant setting for patients with disseminated metastases of human HER-2/neu positive tumors.