Two distinct mechanisms of antitumor activity mediated by the combination of interleukin 2 and monoclonal antibodies.
Previously we described a human B-lymphoma xenotransplantation model in which the immunotherapeutic activity of monoclonal antibodies (mAbs), directed against human B-cell antigens, can be studied. An anti-CD19 mAb of IgG2a subclass was therapeutically active by itself in this model, and its efficacy was increased by simultaneous administration of recombinant interleukin 2 (rIL-2). Immunotherapy with IgG1 or IgG2b isotype variants of an anti-CD19 mAb was ineffective if given alone. We now show that the combination of these ineffective isotype variants with rIL-2 results in significant antitumor effects, although IgG2a anti-CD19 mAb in combination with rIL-2 was therapeutically more active. In vitro studies of the effector mechanisms possibly involved in these treatment modalities indicate that the antitumor activity of IgG1 or IgG2b anti-CD19 mAbs in combination with rIL-2 may be mediated by rIL-2-induced antibody-dependent cellular cytotoxic activity of lymphocytes. The antitumor effect of IgG2a anti-CD19 mAb in combination with rIL-2 may be mediated not only by rIL-2-induced antibody-dependent cellular cytotoxic activity of lymphocytes but also by IgG2a-restricted antitumor activity of monocytes/macrophages. These results may explain the greater in vivo efficacy of treatment with rIL-2 and IgG2a subclass mAb versus treatment with rIL-2 and IgG1 or IgG2b subclass mAbs.
Division of Immunology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Huis, Amsterdam.
W M
WM
Vuist
F
F
van Buitenen
A
A
Hekman
C J
CJ
Melief
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D018941:Antigens, CD19; D000943:Antigens, Differentiation / Q000032:analysis; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology*; D007376:Interleukin-2 / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D011961:Receptors, Fc / Q000032:analysis; D017452:Receptors, IgG; D013154:Spleen / Q000276:immunology; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D018941:Antigens, CD19; D000943:Antigens, Differentiation; D000944:Antigens, Differentiation, B-Lymphocyte; D007074:Immunoglobulin G; D007376:Interleukin-2; D011961:Receptors, Fc; D017452:Receptors, IgG