Anti-CD30-scFv-Fc-IL-2 antibody-cytokine fusion protein that induces resting NK cells to highly efficient cytolysis of Hodgkin's lymphoma derived tumour cells.
The pathogenesis of Hodgkin's disease (HD) is associated with the accumulation of functionally anergic T cells in the near vicinity of the malignant Hodgkin/Reed-Sternberg (H/RS) cell. To stimulate locally the anti-tumour immunity in Hodgkin's disease, we generated an anti-CD30-antibody-interleukin-2 fusion protein (HRS3-scFv-Fc-IL-2) that binds to CD30 constitutively expressed on H/RS cells. The fusion protein is composed of a CD30 binding domain (HRS3-scFv) that is linked via the human IgG hinge-CH2/CH3 domain to human IL-2. The HRS3-scFv-Fc-IL-2 fusion protein is expressed as a 140 kDa homodimer, has binding specificities to both the CD30 antigen and the IL-2 receptor and stimulates proliferation of preactivated T cells in vitro, demonstrating its IL-2 bioactivity. After binding to CD30+ Hodgkin lymphoma cells, HRS3-scFv-Fc-IL-2 moreover induces resting NK cells, but not T cells, to lyse the lymphoma cells with high efficiency. Recruitment of resting NK cells towards a cytolytic immune response against CD30+ lymphoma cells has the potential to build up an effective anti-tumour response despite of Hodgkin's disease associated T-cell anergy and makes the HRS3-scFv-Fc-IL-2 fusion protein suitable for the specific immunotherapy of Hodgkin's lymphoma.
Heuser
Claudia
C
Klinik I für Innere Medizin, Labor Tumorgenetik, Universität zu Köln, and Center for Molecular Medicine Cologne, Köln, Germany.
Guhlke
Stefan
S
Matthies
Alexander
A
Bender
Hans
H
Barth
Stefan
S
Diehl
Volker
V
Abken
Hinrich
H
Hombach
Andreas
A
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002469:Cell Separation; D016207:Cytokines / Q000737:chemistry*; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D006689:Hodgkin Disease / Q000378:metabolism*; D006801:Humans; D007128:Immunoglobulin Fragments / Q000737:chemistry*; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D019169:Jurkat Cells; D017730:Ki-1 Antigen / Q000096:biosynthesis* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D014018:Tissue Distribution
D016207:Cytokines; D018076:DNA, Complementary; D007128:Immunoglobulin Fragments; D007376:Interleukin-2; D017730:Ki-1 Antigen; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins