Evaluation of monoclonal antibody-mediated anti-acute myeloid leukemia immunotherapy in a SCID/hu model.
The therapeutic potential of the IgM complement-fixing murine monoclonal antibody (mAb) PM-81 (anti-CD15) against acute myeloid leukemia (AML) was assessed in a SCID/hu leukemia model. Intraperitoneal (i.p.) injection of NB4 leukemia cells resulted in aggressive growth of leukemia cells in the peritoneal cavity of irradiated SCID/CB-17 mice. Flow cytometric analysis of human CD15, 33 and 45 expression, as well as cytologic examination, revealed that leukemia cells disseminated into the peripheral blood and multiple tissues of the mice. The approximately linear relationship between the injected leukemia cells and the subsequent leukemia cell proliferation provided a reliable model for monitoring the therapeutic effects of immunotherapy. Intraperitoneal injection of the mAb PM-81 markedly suppressed leukemia cell growth in this SCID/leukemia model. Most of the untreated mice died within 35-50 days of leukemia cell inoculation. Four weeks after inoculation of NB4 cells, five of nine mAb PM-81 treated mice had no solid tumor growth and six of nine had no detectable peritoneal exudate leukemia cells as determined by flow cytometry. In contrast, 100% of the mice in the untreated or control mAb groups were found to have both solid and peritoneal leukemia growth. In further experiments designed to evaluate the effects of therapy on survival, 50% (4/8) of PM-81 treated mice survived to 150 days, and had no detectable solid or suspension leukemia cells detectable at necropsy. In contrast, the median survival of untreated or negative control antibody-treated mice was 40 days (comparison to PM-81 treated; p = 0.006 and p = 0.03, respectively). The mechanism of leukemia cell suppression is not likely due to complement fixation since we could not demonstrate in vitro any cytotoxicity mediated by SCID mouse plasma. Further study is required to understand the mechanism of the antileukemia effect of PM-81 in this model.
Zhong
R K
RK
Department of Medicine, Pittsburgh Cancer Institute, University of Pittsburgh, PA 15213, USA.
Donnenberg
A D
AD
Shultz
L D
LD
Swerdlow
S H
SH
Lee
E
E
Rubin
J
J
Kozii
R
R
Chen
J
J
Griffin
D L
DL
Wilson
J
J
Ball
E D
ED
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000032:analysis; D002455:Cell Division; D002884:Chromosomes, Human, Pair 15; D002886:Chromosomes, Human, Pair 17; D003165:Complement System Proteins / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007075:Immunoglobulin M / Q000627:therapeutic use*; D016130:Immunophenotyping; D007167:Immunotherapy; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D017493:Leukocyte Common Antigens / Q000032:analysis; D016256:Lewis X Antigen / Q000032:analysis; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D014178:Translocation, Genetic; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D007075:Immunoglobulin M; D016256:Lewis X Antigen; D003165:Complement System Proteins; D017493:Leukocyte Common Antigens