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 Th1 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 antibody‐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‐γ, a predominant Th1 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. © 2003 Wiley‐Liss, Inc.