Idiotype-cytokine fusion proteins as cancer vaccines. Relative efficacy of IL-2, IL-4, and granulocyte-macrophage colony-stimulating factor.

Abstract

Idiotypic determinants, antigenic sites expressed on the variable region of Ig molecules of malignant B cells, represent tumor-specific Ags but are weak immunogens. We have previously shown that the immunogenicity can be dramatically increased by fusing tumor Id to granulocyte macrophage (GM)-CSF. Here, we demonstrate that fusion proteins with IL-2 or IL-4 can also be highly immunogenic. Co-immunization of these fusion proteins with another Id demonstrated the importance of physical linkage between the cytokine and relevant Ag for this enhancement. All three fusion proteins are capable of eliciting significant levels of specific Abs against the Id without the use of carrier proteins or adjuvants, although the GM-CSF fusion protein appeared to be unique in its ability to induce higher titers of anti-Id Abs in the primary response. Furthermore, the Id-IL-2 fusion protein induced high titers of IgG2a and IgG3 anti-Id Abs, whereas the Id-IL-4 and Id-GM-CSF fusion proteins did not. Despite the differences, tumor protection was comparable in all mice having significant titers of anti-Id Abs, regardless of the fusion protein used. We concluded that Id-cytokine fusion proteins are potent immunogens that can elicit significant antitumor immunity. The general approach of fusing a cytokine to a potential Ag may be applicable to the design of vaccines for immunotherapy of other types of tumors as well as for other pathogens and disease states.