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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
FM Uckun, C Manivel, D Arthur, LM Chelstrom, D Finnegan, L Tuel-Ahlgren, JD Irvin, DE Myers and R Gunther
Department of Therapeutic Radiology-Radiation Oncology, University of
Minnesota Health Sciences Center, Minneapolis.
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)
Volume 79,
Issue 9,
pp. 2201-2214,
05/01/1992
Copyright © 1992 by The American Society of Hematology
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