Anti-idiotype × Anti-LFA-1 Bispecific Antibodies Inhibit Metastasis of B Cell Lymphoma

Abstract

Abs to adhesion molecules can block tumor metastasis. However, they may also block the function of normal cells. To circumvent this adverse effect, we proposed the use of bispecific Abs that bind simultaneously to an adhesion receptor and to a tumor-specific Ag. Such Abs bind more avidly to tumor cells that coexpress both target Ags than to normal cells. The Id of the surface Ig of malignant B lymphocytes is a tumor-specific Ag. We therefore produced a bispecific Ab with specificity to the adhesion molecule LFA-1 and to the Id of the murine B cell lymphoma 38C-13. Here we demonstrate that this Ab blocked liver metastasis in mice carrying primary s.c. tumors and partially inhibited lymph node metastasis. Migration of 38C-13 cells to liver and lymph nodes was inhibited by the bispecific Ab, while migration to spleen was not affected. Hence, the bispecific Ab-mediated reduction in liver and lymph node metastasis resulted at least in part from reduced homing to these organs. In contrast to anti-LFA-1 monospecific Abs, the anti-Id × anti-LFA-1 bispecific Ab did not affect immune responses such as delayed-type hypersensitivity. Hence, bispecific Abs against adhesion molecules and against tumor-specific Ags may selectively block tumor metastasis in a way that may leave much of the immune system intact.

Anti-Idiotype × Anti-CD44 Bispecific Antibodies Inhibit Invasion of Lymphoid Organs by B Cell Lymphoma

“…Therefore, we studied the effect of the bispecific Abs on tumor cell migration. As previously reported by us (19) and by others (43), despite the massive development of 38C-13 lymph node metastases, only a small proportion of the i.v. injected cells migrated to peripheral and mesenteric lymph nodes, suggesting that the entry of a small number of lymphoma cells into lymph nodes is sufficient for development of metastases.…”

“…Our in vitro studies demonstrated that the anti-Id ϫ anti-LFA-1 bispecific Ab selectively blocked LFA-1-mediated adhesion of Id-expressing tumor cells, but had no effect on adhesion of normal lymphocytes (14). Moreover, it abolished liver metastasis in tumor-bearing mice (19). However, despite its dramatic inhibitory effect on liver metastasis, the anti-Id ϫ anti-LFA-1 Ab had only partial effect on dissemination to lymph nodes, and no effect on spleen and bone marrow metastasis.…”

“…into mice, they grow at the site of inoculation and disseminate to different organs (19,29,30). Tumor dissemination is manifested by enlargement of the infiltrated organs, as determined by an increase in organ weight.…”

Colon carcinoma cell interaction with liver sinusoidal endothelium inhibits organ-specific antitumor immunity through interleukin-1-induced mannose receptor in mice

“…LSECs express and secrete ICAM-1, and tumor expression of LFA-1 integrin contributes to hepatic metastasis of lymphoma, leukemia, and breast cancer, 29,30 whereas LFA-1 blockade 31 and ICAM-1-deficient mice 32 can inhibit hepatic metastasis. At present, the role of LFA-1 expression by colon carcinoma cells is unclear, although CD44 induces HT-29 tumor cell adhesion and migration through LFA-1 up-regulation.…”

Golgi Specificity and Development of Autoreactive B Cells

“…Anti-idiotype antibodies against a B cell lymphoma antibody, 38C-13, have been produced by using idiotype conjugated to keyhole limpet hemocyanin (306,307). Anti-idiotypes and bi-specific antibodies have been generated to be used as treatments for lymphomas (308,309). Bi-specific antibodies that bind to an adhesion receptor and tumor specific antigen at the same time are effective in blocking tumor metastasis.…”