Interleukin-12 increases bispecific-antibody-mediated natural killer cell cytotoxicity against human tumors.
The combination of CD16/CD30 bispecific monoclonal antibodies (bi-mAb) and unstimulated human resting natural killer (NK) cells can cure about 50% of mice with severe combined immunodeficiency (SCID) bearing subcutaneously growing established Hodgkin's lymphoma. As interleukin-2 (IL-2) and IL-12 have been shown to increase NK cell activity, we tested the capacity of these cytokines to increase bi-mAb-mediated NK cell cytotoxicity against two types of human tumors (Hodgkin's disease and colorectal carcinoma). Unstimulated NK cells needed a three- to five-times higher antibody concentration than cytokine-stimulated NK cells to exert similar levels of bi-mAb-mediated cytotoxicity. The augmented tumor cell lysis was achieved with IL-12 at considerably lower concentrations than with IL-2 and was associated with a significantly increased bi-mAb-mediated intracellular Ca2+ mobilization. The efficiency of IL-12 in this setting together with its low toxicity make it the ideal candidate for a combination therapy with NK-cell-activating bi-mAb in human tumors that are resistant to standard treatment.
Sahin
U
U
Med. Klinik I, University of Saarland Medical School, Homburg/Saar, Germany.
Kraft-Bauer
S
S
Ohnesorge
S
S
Pfreundschuh
M
M
Renner
C
C
D018033:Antibodies, Bispecific / Q000276:immunology* / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects* / Q000276:immunology; D005069:Evaluation Studies as Topic; D006689:Hodgkin Disease / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D016219:Immunotherapy, Adoptive; D018664:Interleukin-12 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology; D017730:Ki-1 Antigen / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology; D014407:Tumor Cells, Cultured
D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D007376:Interleukin-2; D017730:Ki-1 Antigen; D017452:Receptors, IgG; D018664:Interleukin-12; D002118:Calcium