INHIBITION OF HUMAN B-CELL CHRONIC LYMPHOCYTIC-LEUKEMIA BY A MONOCLONAL-ANTIBODY IN XENOGRAFT MODELS

To establish xenograft models of human B-cell chronic lymphocytic leukemia (CLL), we inoculated 5 x 10(6) D-10-1 cells, a subline of Epstein-Barr virus (EBV)-transformed human B-cell CLL with a marker chromosomal anomaly, into SCID or irradiated nude mice by the intravenous (i.v.) or intraperitoneal (i.p.) route. All i.p. tumor-inoculated mice developed rapidly progressive, lethal ascites tumor, and 100% of i.v. tumor-inoculated mice developed disseminated CLL. All mice died of tumor within 8 weeks of tumor inoculation. Tumor-inoculated SCID mice died earlier with wider tumor dissemination than the tumor-inoculated nude mice. All the tumor-inoculated SCID mice died earlier with wider tumor dissemination than the tumor-inoculated nude mice. All the tumor-inoculated mice had histologically confirmed metastases in lymph nodes, and most of them also had metastases in one or more internal organs. Cytogenetic analysis confirmed the origin of these tumors from the xeno-grafted D-10-1 cells. The D-10-1 cells harvested from the xenografts did not differ from the parent D-10-1 cells harvested from the xenografts did not differ from the parent D-10-1 cells as regards (1) reactivity with 2 monoclonal antigens; (ii) rate of proliferation in vitro; and (iii) sensitivity to the 2 chemotherapeutic agents, methotrexate and adriamycin. Administration of 50 mu g/mouse of DaI B02, and IgG(1) (K) MAB directed against surface-associated antigens of human B-cell CLL, significantly prolonged the survival of D-10-1- inoculated nude and SCID mice. The MAb was more effective in D-10-1-inoculated nude mice than in SCID mice. In all the D-10-1 xenograft models, the effectiveness of DaI BO2 decreased with higher tumor load but increased with the amount of MAb injected. DaI BO2 F(ab)'2 fragment failed to demonstrate any anti-tumor activity in D-10-1-inoculated nude mice. In vitro assays revealed that DaI BO2 had no direct inhibitory effect on D-10-1 cells, but could be cytotoxic towards D-10-1 cells in the presence of splenic cells or peritoneal macrophages from nude and SCID mice, or togeher with rabbit complement. (C) 1994 Wiley-Liss, Inc.