title: An IL12-IL2-antibody fusion protein targeting Hodgkin's lymphoma cells potentiates activation of NK and T cells for an anti-tumor attack.
abstract: Successful immunotherapy of Hodgkin's disease is so far hampered by the striking unresponsiveness of lymphoma infiltrating immune cells. To mobilize both adoptive and innate immune cells for an anti-tumor attack we fused the pro-inflammatory cytokines IL2 and IL12 to an anti-CD30 scFv antibody in a dual cytokine fusion protein to accumulate both cytokines at the malignant CD30(+) Hodgkin/Reed-Sternberg cells in the lymphoma lesion. The tumor-targeted IL12-IL2 fusion protein was superior in activating resting T cells to amplify and secrete pro-inflammatory cytokines compared to targeted IL2 or IL12 alone. NK cells were also activated by the dual cytokine protein to secrete IFN-γ and to lyse target cells. The tumor-targeted IL12-IL2, when applied by i.v. injection to immune-competent mice with established antigen-positive tumors, accumulated at the tumor site and induced tumor regression. Data demonstrate that simultaneous targeting of two cytokines in a spatial and temporal simultaneous fashion to pre-defined tissues is feasible by a dual-cytokine antibody fusion protein. In the case of IL12 and IL2, this produced superior anti-tumor efficacy implying the strategy to muster a broader immune cell response in the combat against cancer.
authors.affiliation: Department I of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Jahn
authors.forename: Martin
authors.initials: M
authors.lastname: Zuther
authors.forename: Björn
authors.initials: B
authors.lastname: Friedrichs
authors.forename: Claudia
authors.initials: C
authors.lastname: Heuser
authors.forename: Stefan
authors.initials: S
authors.lastname: Guhlke
authors.forename: Hinrich
authors.initials: H
authors.lastname: Abken
authors.forename: Andreas A
authors.initials: AA
authors.lastname: Hombach
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D006689:Hodgkin Disease / Q000276:immunology* / Q000628:therapy*; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017730:Ki-1 Antigen / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D057127:Single-Chain Antibodies / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D007376:Interleukin-2; D017730:Ki-1 Antigen; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; D018664:Interleukin-12