Anti-CD30-IL-12 antibody-cytokine fusion protein that induces IFN-gamma 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-gamma, 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.
Heuser
Claudia
C
Klinik I für Innere Medizin, Labor für Tumorgenetik, Universität zu Köln, Köln, Germany.|Zentrum für Molekulare Medizin Köln (ZMMK), Universität zu Köln, Köln, Germany.
Diehl
Volker
V
Klinik I für Innere Medizin, Labor für Tumorgenetik, Universität zu Köln, Köln, Germany.|Zentrum für Molekulare Medizin Köln (ZMMK), Universität zu Köln, Köln, Germany.
Abken
Hinrich
H
Klinik I für Innere Medizin, Labor für Tumorgenetik, Universität zu Köln, Köln, Germany.|Zentrum für Molekulare Medizin Köln (ZMMK), Universität zu Köln, Köln, Germany.
Hombach
Andreas
A
Klinik I für Innere Medizin, Labor für Tumorgenetik, Universität zu Köln, Köln, Germany.|Zentrum für Molekulare Medizin Köln (ZMMK), Universität zu Köln, Köln, Germany.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D017931:DNA Primers / Q000737:chemistry; D005455:Fluorescent Antibody Technique; D006689:Hodgkin Disease / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism*; D017730:Ki-1 Antigen / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D010957:Plasmids; D016133:Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins / Q000276:immunology*; D016539:Reed-Sternberg Cells / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism; D014162:Transfection
D000911:Antibodies, Monoclonal; D017931:DNA Primers; D017730:Ki-1 Antigen; D011993:Recombinant Fusion Proteins; D018664:Interleukin-12; D007371:Interferon-gamma