The
melanoma reactive chimeric 14.18 (
ch14.18) antibody can mediate enhanced in vitro lysis of human M-21
melanoma cells. This study analyzes the antitumor effects and the in vivo binding of
ch14.18 antibody with M-21
melanoma cells in
severe combined immunodeficiency (SCID) mice. Outgrowth of
tumors was prevented in 6/6 animals by the simultaneous
subcutaneous injection of peripheral blood mononuclear cells (PBMC) [3 x 10(6) cells (2 animals); 10 x 10(6) cells (2 animals); and 30 x 10(6) cells (2 animals)], with 0.5 mg
ch14.18, 1,500 U
interleukin 2 (IL-2), and 10(6) M-21 cells. In contrast, 7 of 7 control mice that received M-21 cells alone, 7 of 7 mice that received M-21 cells and
ch14.18, and 5 of 6 mice that received M-21 cells plus PBMC plus
IL-2, grew subcutaneous
tumors. The in vivo localization of
ch14.18 was then evaluated in an intraperitoneal (i.p.)
tumor model, where 0.3 cm
melanoma nodules develop within 3 weeks after the i.p. administration of M-21 cells. Flow cytometric and immunohistochemical analysis revealed the GD2
antigen present throughout the
tumor nodule. Intraperitoneal administration of 0.01, 0.1, or 1.0 mg of
ch14.18 to SCID mice previously engrafted i.p. with M-21 cells resulted in detectable
ch14.18 binding to
tumor cells in vivo within 10 hours of antibody administration.
Ch14.18 penetration was limited to approximately 20 cell layers, demonstrating that
ch14.18 has limited access to some cells in large
tumor nodules. This study demonstrates that the addition of
ch14.18 to
IL-2 and human effector cells can result in significant antitumor activity by preventing the establishment of
tumor nodules. These results suggest that clinical testing of
IL-2 plus
ch14.18 might be most effective if used in the setting of microscopic residual disease.
Therapies that enhance
ch14.18 penetration into
tumor nodules should be evaluated with
ch14.18 for patients with advanced
melanoma.