Activation of human effector cells by a tumor reactive recombinant anti-ganglioside GD2 interleukin-2 fusion protein (ch14.18-IL2).
Cytotoxic effector cells interact with target cells through various mechanisms. CTLs use the antigen-specific T cell receptor, whereas Fc receptor-positive natural killer cells use this receptor to interact with antibody-coated target cells. We evaluated the tumor-binding and lymphocyte-activating capability of a recombinant fusion protein consisting of a tumor-selective human/mouse chimeric anti-ganglioside GD2 antibody (ch14.18) and recombinant human interleukin-2 (IL2) (ch14.18-IL2). This fusion protein bound specifically to GD2-positive melanoma and neuroblastoma tumor cell lines, and its IL2 component stimulated in vitro proliferation of an IL2-dependent cell line, as well as peripheral blood mononuclear cells, in healthy control individuals and in cancer patients receiving continuous infusion of IL2. The IL2 presented by the fusion protein, when bound to tumor cells, induced proliferation of IL2-responsive cells as well as a comparable amount of soluble IL2 did. This suggests that localization of IL2 at the site of contact between tumor and effector cells is an effective way of presenting this cytokine to IL2-responsive cells. The ch14.18-IL2 fusion protein also mediated antibody-dependent cellular cytotoxicity with Fc receptor-positive effector cells to an extent similar to ch14.18. These results, together with those of previous studies documenting antitumor efficacy against human tumor xenografts in SCID mice and GD2-positive murine tumors in immunocompetent syngeneic mice, suggest that the ch14.18-IL2 fusion protein should be tested in Phase I and II trials in patients with GD2-positive tumors.
Hank
J A
JA
Department of Human Oncology, University of Wisconsin-Madison, Madison, Wisconsin 53792, USA.
Surfus
J E
JE
Gan
J
J
Jaeger
P
P
Gillies
S D
SD
Reisfeld
R A
RA
Sondel
P M
PM
D000818:Animals; D000906:Antibodies / Q000235:genetics / Q000627:therapeutic use; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005732:Gangliosides / Q000276:immunology*; D006801:Humans; D000922:Immunotoxins / Q000235:genetics / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000378:metabolism / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D015375:Receptors, Interleukin-2 / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000906:Antibodies; D005732:Gangliosides; D000922:Immunotoxins; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; C019403:ganglioside, GD2