|
|
 Previous Article | Table of Contents | Next Article 
Anti-MY9-blocked-ricin: an immunotoxin for selective targeting of acute
myeloid leukemia cells
DC Roy, JD Griffin, M Belvin, WA Blattler, JM Lambert and J Ritz
Division of Tumor Immunology, Dana-Farber Cancer Institute, Boston, MA.
The use of immunotoxins (IT) to selectively destroy acute myeloid leukemia
(AML) cells in vivo or in vitro is complicated by both the antigenic
similarity of AML cells to normal progenitor cells and the difficulty of
producing a sufficiently toxic conjugate. The monoclonal antibody (MoAb)
anti-MY9 is potentially ideal for selective recognition of AML cells
because it reacts with an antigen (CD33) found on clonogenic AML cells from
greater than 80% of cases and does not react with normal pluripotent stem
cells. In this study, we describe an immunotoxin that is selectively active
against CD33+ AML cells: Anti- MY9-blocked-Ricin (Anti-MY9-bR), comprised
of anti-MY9 conjugated to a modified whole ricin that has its nonspecific
binding eliminated by chemical blockage of the galactose binding domains of
the B-chain. A limiting dilution assay was used to measure elimination of
HL-60 leukemic cells from a 20-fold excess of normal bone marrow cells.
Depletion of CD33+ HL-60 cells was found to be dependent on the
concentration of Anti-MY9-bR and on the duration of incubation with IT at
37 degrees C. More than 4 logs of these leukemic cells were specifically
depleted following short exposure to high concentrations (10(-8) mol/L) of
Anti-MY9-bR. Incubation with much lower concentrations of Anti-MY9-bR
(10(-10) mol/L), as compatible with in vivo administration, resulted in 2
logs of depletion of HL-60 cells, but 48 to 72 hours of continuous exposure
were required. Anti-MY9-bR was also shown to be toxic to primary AML cells,
with depletion of greater than 2 logs of clonogenic cells following
incubation with Anti- MY9-bR 10(-8) mol/L at 37 degrees C for 5 hours.
Activity of Anti-MY9- bR could be blocked by unconjugated Anti-MY9 but not
by galactose. As expected, Anti-MY9-bR was toxic to normal colony-forming
unit granulocyte-monocyte (CFU-GM), which expresses CD33, in a
concentration- and time-dependent manner, and also to burst-forming
unit-erythroid and CFU-granulocyte, erythroid, monocyte, megakaryocyte,
although to a lesser extent. When compared with anti-MY9 and complement
(C'), Anti- MY9-bR could be used in conditions that provided more effective
depletion of AML cells with substantially less depletion of normal CFU- GM.
Therefore, Anti-MY9-bR may have clinical utility for in vitro purging of
AML cells from autologous marrow when used at high IT concentrations for
short incubation periods. Much lower concentrations of Anti-MY9-bR that can
be maintained for longer periods may be useful for elimination of AML cells
in vivo.
Volume 77,
Issue 11,
pp. 2404-2412,
06/01/1991
Copyright © 1991 by The American Society of Hematology
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
R. Schnell, P. Borchmann, J. O. Staak, J. Schindler, V. Ghetie, E. S. Vitetta, and A. Engert
Clinical evaluation of ricin A-chain immunotoxins in patients with Hodgkin's lymphoma
Ann. Onc.,
May 1, 2003;
14(5):
729 - 736.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Borchmann, R. Schnell, I. Fuss, O. Manzke, T. Davis, L. D. Lewis, D. Behnke, C. Wickenhauser, P. Schiller, V. Diehl, et al.
Phase 1 trial of the novel bispecific molecule H22xKi-4 in patients with refractory Hodgkin lymphoma
Blood,
October 16, 2002;
100(9):
3101 - 3107.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Schnell, O. Staak, P. Borchmann, C. Schwartz, B. Matthey, H. Hansen, J. Schindler, V. Ghetie, E. S. Vitetta, V. Diehl, et al.
A Phase I Study with an Anti-CD30 Ricin A-Chain Immunotoxin (Ki-4.dgA) in Patients with Refractory CD30+ Hodgkin's and Non-Hodgkin's Lymphoma
Clin. Cancer Res.,
June 1, 2002;
8(6):
1779 - 1786.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. E. Hogge, C. L. Willman, R. J. Kreitman, M. Berger, P. D. Hall, K. J. Kopecky, C. McLain, E. P. Tagge, C. J. Eaves, and A. E. Frankel
Malignant Progenitors From Patients With Acute Myelogenous Leukemia Are Sensitive to a Diphtheria Toxin-Granulocyte-Macrophage Colony-Stimulating Factor Fusion Protein
Blood,
July 15, 1998;
92(2):
589 - 595.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. E. Frankel, P. D. Hall, C. Burbage, J. Vesely, M. Willingham, K. Bhalla, and R. J. Kreitman
Modulation of the Apoptotic Response of Human Myeloid Leukemia Cells to a Diphtheria Toxin Granulocyte-Macrophage Colony-Stimulating Factor Fusion Protein
Blood,
November 1, 1997;
90(9):
3654 - 3661.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Engert, V. Diehl, R. Schnell, A. Radszuhn, M.-T. Hatwig, S. Drillich, G. Schon, H. Bohlen, H. Tesch, M.-L. Hansmann, et al.
A Phase-I Study of an Anti-CD25 Ricin A-Chain Immunotoxin (RFT5-SMPT-dgA) in Patients With Refractory Hodgkin's Lymphoma
Blood,
January 15, 1997;
89(2):
403 - 410.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. O. Armitage
Bone Marrow Transplantation
N. Engl. J. Med.,
March 24, 1994;
330(12):
827 - 838.
[Full Text]
|
|
|
|
|
