Establishment of new SCID and nude mouse models of human B leukemia/lymphoma and effective therapy of the tumors with immunotoxin and monoclonal antibody: marked difference between the SCID and nude mouse models in the antitumor efficacy of monoclonal antibody.
BALL-1, a human B leukemia/lymphoma cell line, was transplanted into nude and SCID mice under various conditions. The transplantation was substantially improved by preadaptation of BALL-1 by serial passages in newborn and young nude mice. We were able to establish the desirable conditions where 100% of SCID and nude mice that were inoculated i.p. with various doses of the adapted BALL-1 (termed BALL-1a) developed tumors. Tumors in SCID mice were disseminated to various tissues in a manner analogous to tumors in patients with B leukemia/lymphoma, whereas tumors in nude mice were not as widely disseminated and grew mainly as ascites. Flow cytometric analyses showed that all of the 11 tested cell surface markers of the parental BALL-1 were well maintained on the tumor cells recovered from the SCID and nude mice. The utility of the developed tumor models for the therapeutic studies was investigated by i.p. or i.v. administration of an anti-B leukemia/lymphoma monoclonal antibody, termed SN7 (IgG1 kappa), and SN7 immunotoxin (IT) that was prepared by conjugating SN7 to ricin A chain (RA) or deglycosylated RA (dgRA). In the nude mouse model study, SN7-RA that had been administered i.p. suppressed the tumor growth completely in all of the treated mice (n = 5) without any sign of tumor or undesirable side effects for as long as followed (i.e., 350 days), whereas unconjugated SN7 showed only a slight therapeutic effect. A control RA conjugate was not effective. In the SCID mouse model studies, several sets of experiments were carried out by i.p. or i.v. administration of IT, monoclonal antibody, or control IT. In the first three sets of experiments, SCID mice inoculated with 1.1 x 10(6) BALL-1a cells received an i.p. administration of phosphate-buffered saline or three different doses (i.e., 4 x 10 micrograms, 4 x 20 micrograms, and 4 x 30 micrograms) of therapeutic agents (SN7-RA and SN7). Virtually an identical result was obtained from the three experiments. All of the phosphate-buffered saline control group mice (n = 15) died within 35 days post tumor inoculation. In contrast, all of the mice that were treated with SN7-RA (n = 19) or with SN7 (n = 15) survived for as long as followed (i.e., 250 days). However, the unconjugated SN7 was less effective than SN7 IT for tumor suppression in SCID mice that were inoculated with a larger tumor burden (i.e., 4 x 10(7) BALL-1a cells).(ABSTRACT TRUNCATED AT 400 WORDS)
Kawata
A
A
Department of Molecular Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263.
Yoshida
M
M
Okazaki
M
M
Yokota
S
S
Barcos
M
M
Seon
B K
BK
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D015448:Leukemia, B-Cell / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D012276:Ricin / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D012276:Ricin