An anti-MUC1-antibody-interleukin-2 fusion protein that activates resting NK cells to lysis of MUC1-positive tumour cells.
MUC1 mucin is aberrantly glycosylated and overexpressed in a number of epithelial malignancies and is therefore a promising tumour-associated antigen for target-directed immunotherapy of a panel of malignant diseases. In MUC1-positive tumours, MHC class I expression is frequently downregulated and MUC1-specific cytotoxic T cells (CTLs) are either not available or in a state of anergy allowing tumour growth without limitation by CTL control. To activate lymphocytes and natural killer (NK) cells, we here generated an anti-MUC1-scFv-IL2 fusion protein (C595scFv-Fc-IL2) that contains the C595 single-chain antibody for MUC1 binding, the human IgG1 CH2CH3 domain for protein dimerisation, and interleukin-2 (IL2) for activation of immunological effector cells. The fusion protein binds to MUC1-derived peptides and to MUC1-positive tumour cells with the same specificity as does the C595 monoclonal antibody. Bound to MUC1, the C595scFv-Fc-IL2 fusion protein stimulates proliferation of human activated lymphocytes in vitro. Upon binding to MUC1-positive MCF7 breast carcinoma cells, moreover, the fusion protein activates resting NK cells to tumour cell lysis. These properties make the C595scFv-Fc-IL2 fusion protein a suitable candidate for the immunotherapy of MUC1-positive tumours.
Heuser
C
C
Lab. Tumorgenetik, Klinik I für Innere Medizin, Klinikum der Universität zu Köln, Joseph-Stelzmann-Str. 9, D-50931 Köln, Germany.
Ganser
M
M
Hombach
A
A
Brand
H
H
Denton
G
G
Hanisch
F-G
FG
Abken
H
H
D000911:Antibodies, Monoclonal; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D017931:DNA Primers / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007111:Immunity, Cellular; D007376:Interleukin-2 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D018396:Mucin-1 / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D010957:Plasmids; D016133:Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014614:Vaccines, Synthetic / Q000276:immunology
D000911:Antibodies, Monoclonal; D017931:DNA Primers; D007376:Interleukin-2; D018396:Mucin-1; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D014614:Vaccines, Synthetic