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 leuk emia (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 chromosom al anomaly, into SCID or irradiated nude mice by the intravenous (i.v. ) or intraperitoneal (i.p.) route. All i.p. tumor-inoculated mice deve loped rapidly progressive, lethal ascites tumor, and 100% of i.v. tumo r-inoculated mice developed disseminated CLL. All mice died of tumor w ithin 8 weeks of tumor inoculation. Tumor-inoculated SCID mice died ea rlier with wider tumor dissemination than the tumor-inoculated nude mi ce. All the tumor-inoculated SCID mice died earlier with wider tumor d issemination than the tumor-inoculated nude mice. All the tumor-inocul ated mice had histologically confirmed metastases in lymph nodes, and most of them also had metastases in one or more internal organs. Cytog enetic analysis confirmed the origin of these tumors from the xeno-gra fted 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 ad riamycin. Administration of 50 mu g/mouse of DaI B02, and IgG(1) (K) M AB directed against surface-associated antigens of human B-cell CLL, s ignificantly prolonged the survival of D-10-1- inoculated nude and SCI D 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 o f DaI BO2 decreased with higher tumor load but increased with the amou nt 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 r evealed 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 w ith rabbit complement. (C) 1994 Wiley-Liss, Inc.