Anti-CD30-IL-12 antibody-cytokine fusion protein that induces IFN-Γ secretion of T cells and NK cell-mediated lysis of Hodgkin's lymphoma-derived tumor cells

Interleukin-12 (IL-12) is a disulfide-linked p40-p35 heterodimeric cytokine and plays a key role in linking innate cellular immunity to an adaptive ThI response against pathogens and tumor cells and in counteracting a Th2 immune response. The pathogenesis of Hodgkin's disease (HD) is partially attributed to a Th2 dominance associated with functional anergy of T cells that accumulate in the near vicinity to the malignant Hodgkin/Reed-Sternberg (H/RS) cells. To revert Th2 polarization in the tumor lesion, we generated an anti-CD30-IL-12 anti body-cytokine fusion protein that binds to CD30 on H/RS cells and is composed of a CD30 binding domain (HRS3-scFv) linked to p40-p35 murine single chain IL-12. The HRS3-scFv-hi-IL-12 fusion protein is expressed as a 110 kD polypeptide, can be purified by affinity chromatography, and has binding specificities to both the CD30 antigen and the IL-12 receptor. After binding to CD30(+) H/RS cells, the fusion protein stimulates T cells to secrete IFN-gamma, a predominant ThI cytokine, and induces NK cells to lyse CD30+ cells with high efficiency. These properties make the HRS3-scFv-hi-IL-12 fusion protein suitable for the specific immunotherapy of Hodgkin's lymphoma. (C) 2003 Wiley-Liss, Inc.