Bypassing tumor-specific and bispecific antibodies: triggering of antitumor immunity by expression of anti-FcgammaR scFv on cancer cell surface.
We have developed a novel immunostimulatory molecule against tumor cells, composed of an anti-FcgammaRIII (CD16) scFv fused to the platelet-derived growth factor receptor (PDGFR) transmembrane region. This fusion molecule was stably expressed on the tumor cell surface and retained the ability of the parental antibody to bind soluble CD16. Tumor cells expressing anti-CD16 scFv triggered the release of IL-2 by Jurkat-CD 16/gamma cells and of TNFalpha by monocytes when co-cultured with these cells. Furthermore, NK cells could kill scFv-transfected HLA+ class I H1299 lung carcinoma tumor cells, but not the parental cells, indicating that anti-CD16 scFv tumor expression prevents the killer inhibitory receptor (KIR)-mediated inhibition of NK cell cytotoxicity. This anti-CD16 scFv tumor expression also enhanced tumor phagocytosis by IFNgamma-activated macrophages, a mechanism known to induce a protective long-term adaptative immunity to tumors. In vivo Winn tests performed in SCID mice showed that the expression of anti-CD16 scFv on tumor cells, but not of the negative control anti-phOx scFv, prevented tumor cell growth. Thus, expression of FcR antibodies or other FcR-specific ligands on tumor cells represents a novel and potent antibody-based gene therapy approach, which may have clinical applications in cancer
Gruel
N
N
Laboratoire de Biotecnologie des Anticorps, Institut Curie, Paris, France.
Fridman
W H
WH
Teillaud
J L
JL
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology / Q000628:therapy*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D017452:Receptors, IgG / Q000235:genetics*; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000276:immunology*
D007376:Interleukin-2; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D017479:Receptors, Platelet-Derived Growth Factor