In vivo efficacy of B43 (anti-CD19)-pokeweed antiviral protein immunotoxin against human pre-B cell acute lymphoblastic leukemia in mice with severe combined immunodeficiency.
A highly aggressive subclone of the human CALLA+C mu+ pre-B acute lymphoblastic leukemia (ALL) cell line NALM-6 (designated NALM-6-UM1) caused disseminated and fatal leukemia in CB.17 mice with severe combined immunodeficiency (SCID). An intravenous challenge with 1 x 10(6) (NALM-6-UM1 cells caused 15 of 27 (56%) SCID mice to become paraplegic at 31 +/- 2 days (median = 33 days) and 27 of 27 (100%) mice to die of disseminated leukemia at 38 +/- 1 days (median = 39 days). We used this SCID mouse model of aggressive human pre-B ALL to evaluate the in vivo antileukemic efficacy of B43 (anti-CD19)-pokeweed antiviral protein (PAP) immunotoxin. A 3-day treatment with nontoxic doses of B43-PAP markedly reduced the incidence of paraplegia and improved event-free survival (EFS) in SCID mice challenged with 1 x 10(6) NALM-6-UM1 pre-B ALL cells, as reflected by significantly higher cumulative proportions of mice free of paraplegia or alive at 1 to 7 months, as compared with phosphate-buffered saline (PBS) treated control mice. The Kaplan-Meier estimates and standard errors of the probability of developing paraplegia after inoculation of 1 x 10(6) NALM-6-UM1 cells was 64% +/- 10% for PBS-treated mice (median time to paraplegia = 37 days) (N = 27), 18% +/- 8% for mice treated with 15 micrograms B43-PAP (5 micrograms/mouse/d x 3 days) (N = 23) and 5% +/- 5% for mice treated with 30 micrograms B43-PAP (10 micrograms/mouse/d x 3 days) (N = 21). While 27 of 27 PBS-treated control SCID mice died of leukemia at 38 +/- 1 days (range = 24 to 54 days), only 16 of 44 B43-PAP-treated mice developed leukemia at 74 +/- 12 days (range = 30 to 182 days), consistent with greater than or equal to 6 logs kill of clonogenic NALM-6-UM1 cells in 64% of SCID mice. The Kaplan-Meier estimates and standard errors of the probability of long-term EFS after inoculation of 1 x 10(6) NALM-6-UM1 cells were 65% +/- 10% for mice treated with 15 micrograms B43-PAP and 60% +/- 11% for mice treated with 30 micrograms B43-PAP with a median survival time of greater than 7 months for both groups. In contrast, neither unconjugated B43 monoclonal antibody nor the anti-T-cell immunotoxin G17.2 (anti-CD4)-PAP decreased the incidence of paraplegia or improved EFS.(ABSTRACT TRUNCATED AT 400 WORDS)
Uckun
F M
FM
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Health Sciences Center, Minneapolis.
Manivel
C
C
Arthur
D
D
Chelstrom
L M
LM
Finnegan
D
D
Tuel-Ahlgren
L
L
Irvin
J D
JD
Myers
D E
DE
Gunther
R
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000032:analysis / Q000276:immunology*; D018941:Antigens, CD19; D000943:Antigens, Differentiation / Q000032:analysis; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000032:analysis; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D002051:Burkitt Lymphoma / Q000235:genetics / Q000628:therapy*; D002869:Chromosome Aberrations; D006649:Histocompatibility Antigens / Q000032:analysis; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D017493:Leukocyte Common Antigens; D051379:Mice; D016513:Mice, SCID; D009699:N-Glycosyl Hydrolases; D015260:Neprilysin; D010940:Plant Proteins / Q000627:therapeutic use*; D054789:Ribosome Inactivating Proteins, Type 1
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018941:Antigens, CD19; D000943:Antigens, Differentiation; D000944:Antigens, Differentiation, B-Lymphocyte; D000951:Antigens, Neoplasm; D000972:Antineoplastic Agents, Phytogenic; D006649:Histocompatibility Antigens; D000922:Immunotoxins; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D017493:Leukocyte Common Antigens; D009699:N-Glycosyl Hydrolases; C024275:pokeweed antiviral protein; D015260:Neprilysin