Mechanism of antitumor activity of a single-chain interleukin-12 IgG3 antibody fusion protein (mscIL-12.her2.IgG3).
We have constructed an antibody interleukin-12 (IL-12) fusion protein (mscIL-12.her2.IgG3) that demonstrates significant antitumor activity against the murine carcinoma CT26-expressing human HER2/neu. We now report that this antitumor activity is dose dependent and comparable to or better than recombinant murine IL-12 (rMuIL-12) using subcutaneous and metastatic models of disease. The antitumor activity of mscIL-12.her2.IgG3 is reduced in Rag2 knockout mice, suggesting that T cells play a role in tumor rejection. In SCID-beige mice, the antitumor activity is further reduced, suggesting that natural killer (NK) cells or macrophages or both are also important. The isotype of the antibody response to HER2/neu is consistent with a switch from a Th2 to a Th1 immune response and the infiltration of mononuclear cell in tumors from mice treated with mscIL-12.her2.IgG3. Immunohistochemistry reveals that mscIL-12.her2.IgG3 is antiangiogenic. Thus, the mechanism of the antitumor activity exhibited by mscIL-12.her2.IgG3 is highly complex and involves a combination of T and NK cell activity, a switch to a Th1 immune response, and antiantiogenic activity. This is the first study comparing the in vivo antitumor activity of an antibody-IL-12 fusion protein and free IL-12. Our results suggest that antibody-IL-12 fusion proteins may be useful for the treatment of human cancer.
Peng
L S
LS
Department of Microbiology, Immunology and Molecular Genetics and the Molecular Biology Institute, University of California, Los Angeles, CA 90095-1489, USA.
Penichet
M L
ML
Dela Cruz
J S
JS
Sampogna
S L
SL
Morrison
S L
SL
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000912:Antibodies, Neoplasm / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D017252:CD3 Complex / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D018734:Genes, erbB-2 / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology; D008099:Liver / Q000276:immunology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016513:Mice, SCID; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D014018:Tissue Distribution
D020533:Angiogenesis Inhibitors; D000912:Antibodies, Neoplasm; D017252:CD3 Complex; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; D011993:Recombinant Fusion Proteins; C064655:V(D)J recombination activating protein 2; D018664:Interleukin-12