Humanized M195 monoclonal antibody conjugated to recombinant gelonin: An anti-CD33 immunotoxin with antileukemic activity

Lance C. Pagliaro, Baoshun Liu, Reinhold Munker, Michael Andreeff, Emil J. Freireich, David A. Scheinberg, Michael G. Rosenblum

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

The recently characterized immunotoxin HuM195-gelonin consists of a humanized anti-CD33 monoclonal antibody conjugated to the single-chain plant toxin gelonin. Binding of the immunotoxin to hematopoietic cells that express the CD33 differentiation antigen has been demonstrated and results in cytotoxicity due to ribosomal inactivation by gelonin. Blast cells from most patients with acute myelogenous leukemia express CD33, whereas normal stem cells necessary for maintenance of hematopoiesis do not. We asked whether an immunoconjugate using recombinant gelonin rather than plant gelonin is toxic to acute myelogenous leukemia (AML) cell lines and primary AML blasts obtained from patients and exposed to the immunotoxin in vitro. The CD33(pos) cell lines HL60, OCI/AML2, and OCI/AML5 showed decreased proliferation when exposed to immunotoxin for 24-72 h. The CD33(neg) cell line OCI/AML3 was relatively resistant to HuM195, and all cell lines were resistant to equimolar concentrations of unconjugated antibody and gelonin. Primary blast cultures from seven patients with AML had CD33 detectable on 75.7-99.8% of cells by flow cytometry, and all showed dose-dependent decreases in clonogenic cell survival during 24-h incubation with the immunotoxin. Cells selected for low CD33 expression by cell sorting or by prolonged incubation with immunotoxin could reexpress CD33 at baseline levels and remained sensitive to immunotoxin. We conclude that humanized M195 conjugated to recombinant gelonin has antileukemic activity and should be considered for clinical testing in Phase I trials.

Original languageEnglish (US)
Pages (from-to)1971-1976
Number of pages6
JournalClinical Cancer Research
Volume4
Issue number8
StatePublished - Aug 1998
Externally publishedYes

Fingerprint

Immunotoxins
Acute Myeloid Leukemia
Cell Line
Sialic Acid Binding Ig-like Lectin 3
Immunoconjugates
Poisons
Differentiation Antigens
Hematopoiesis
monoclonal antibody M195
Gelonium multiflorum GEL protein
Cell Survival
Flow Cytometry
Stem Cells
Monoclonal Antibodies
Maintenance
Antibodies

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Pagliaro, L. C., Liu, B., Munker, R., Andreeff, M., Freireich, E. J., Scheinberg, D. A., & Rosenblum, M. G. (1998). Humanized M195 monoclonal antibody conjugated to recombinant gelonin: An anti-CD33 immunotoxin with antileukemic activity. Clinical Cancer Research, 4(8), 1971-1976.

Humanized M195 monoclonal antibody conjugated to recombinant gelonin : An anti-CD33 immunotoxin with antileukemic activity. / Pagliaro, Lance C.; Liu, Baoshun; Munker, Reinhold; Andreeff, Michael; Freireich, Emil J.; Scheinberg, David A.; Rosenblum, Michael G.

In: Clinical Cancer Research, Vol. 4, No. 8, 08.1998, p. 1971-1976.

Research output: Contribution to journalArticle

Pagliaro, LC, Liu, B, Munker, R, Andreeff, M, Freireich, EJ, Scheinberg, DA & Rosenblum, MG 1998, 'Humanized M195 monoclonal antibody conjugated to recombinant gelonin: An anti-CD33 immunotoxin with antileukemic activity', Clinical Cancer Research, vol. 4, no. 8, pp. 1971-1976.
Pagliaro LC, Liu B, Munker R, Andreeff M, Freireich EJ, Scheinberg DA et al. Humanized M195 monoclonal antibody conjugated to recombinant gelonin: An anti-CD33 immunotoxin with antileukemic activity. Clinical Cancer Research. 1998 Aug;4(8):1971-1976.
Pagliaro, Lance C. ; Liu, Baoshun ; Munker, Reinhold ; Andreeff, Michael ; Freireich, Emil J. ; Scheinberg, David A. ; Rosenblum, Michael G. / Humanized M195 monoclonal antibody conjugated to recombinant gelonin : An anti-CD33 immunotoxin with antileukemic activity. In: Clinical Cancer Research. 1998 ; Vol. 4, No. 8. pp. 1971-1976.
@article{0123339ccfcc47aebfe2315ea2ead53a,
title = "Humanized M195 monoclonal antibody conjugated to recombinant gelonin: An anti-CD33 immunotoxin with antileukemic activity",
abstract = "The recently characterized immunotoxin HuM195-gelonin consists of a humanized anti-CD33 monoclonal antibody conjugated to the single-chain plant toxin gelonin. Binding of the immunotoxin to hematopoietic cells that express the CD33 differentiation antigen has been demonstrated and results in cytotoxicity due to ribosomal inactivation by gelonin. Blast cells from most patients with acute myelogenous leukemia express CD33, whereas normal stem cells necessary for maintenance of hematopoiesis do not. We asked whether an immunoconjugate using recombinant gelonin rather than plant gelonin is toxic to acute myelogenous leukemia (AML) cell lines and primary AML blasts obtained from patients and exposed to the immunotoxin in vitro. The CD33(pos) cell lines HL60, OCI/AML2, and OCI/AML5 showed decreased proliferation when exposed to immunotoxin for 24-72 h. The CD33(neg) cell line OCI/AML3 was relatively resistant to HuM195, and all cell lines were resistant to equimolar concentrations of unconjugated antibody and gelonin. Primary blast cultures from seven patients with AML had CD33 detectable on 75.7-99.8{\%} of cells by flow cytometry, and all showed dose-dependent decreases in clonogenic cell survival during 24-h incubation with the immunotoxin. Cells selected for low CD33 expression by cell sorting or by prolonged incubation with immunotoxin could reexpress CD33 at baseline levels and remained sensitive to immunotoxin. We conclude that humanized M195 conjugated to recombinant gelonin has antileukemic activity and should be considered for clinical testing in Phase I trials.",
author = "Pagliaro, {Lance C.} and Baoshun Liu and Reinhold Munker and Michael Andreeff and Freireich, {Emil J.} and Scheinberg, {David A.} and Rosenblum, {Michael G.}",
year = "1998",
month = "8",
language = "English (US)",
volume = "4",
pages = "1971--1976",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "8",

}

TY - JOUR

T1 - Humanized M195 monoclonal antibody conjugated to recombinant gelonin

T2 - An anti-CD33 immunotoxin with antileukemic activity

AU - Pagliaro, Lance C.

AU - Liu, Baoshun

AU - Munker, Reinhold

AU - Andreeff, Michael

AU - Freireich, Emil J.

AU - Scheinberg, David A.

AU - Rosenblum, Michael G.

PY - 1998/8

Y1 - 1998/8

N2 - The recently characterized immunotoxin HuM195-gelonin consists of a humanized anti-CD33 monoclonal antibody conjugated to the single-chain plant toxin gelonin. Binding of the immunotoxin to hematopoietic cells that express the CD33 differentiation antigen has been demonstrated and results in cytotoxicity due to ribosomal inactivation by gelonin. Blast cells from most patients with acute myelogenous leukemia express CD33, whereas normal stem cells necessary for maintenance of hematopoiesis do not. We asked whether an immunoconjugate using recombinant gelonin rather than plant gelonin is toxic to acute myelogenous leukemia (AML) cell lines and primary AML blasts obtained from patients and exposed to the immunotoxin in vitro. The CD33(pos) cell lines HL60, OCI/AML2, and OCI/AML5 showed decreased proliferation when exposed to immunotoxin for 24-72 h. The CD33(neg) cell line OCI/AML3 was relatively resistant to HuM195, and all cell lines were resistant to equimolar concentrations of unconjugated antibody and gelonin. Primary blast cultures from seven patients with AML had CD33 detectable on 75.7-99.8% of cells by flow cytometry, and all showed dose-dependent decreases in clonogenic cell survival during 24-h incubation with the immunotoxin. Cells selected for low CD33 expression by cell sorting or by prolonged incubation with immunotoxin could reexpress CD33 at baseline levels and remained sensitive to immunotoxin. We conclude that humanized M195 conjugated to recombinant gelonin has antileukemic activity and should be considered for clinical testing in Phase I trials.

AB - The recently characterized immunotoxin HuM195-gelonin consists of a humanized anti-CD33 monoclonal antibody conjugated to the single-chain plant toxin gelonin. Binding of the immunotoxin to hematopoietic cells that express the CD33 differentiation antigen has been demonstrated and results in cytotoxicity due to ribosomal inactivation by gelonin. Blast cells from most patients with acute myelogenous leukemia express CD33, whereas normal stem cells necessary for maintenance of hematopoiesis do not. We asked whether an immunoconjugate using recombinant gelonin rather than plant gelonin is toxic to acute myelogenous leukemia (AML) cell lines and primary AML blasts obtained from patients and exposed to the immunotoxin in vitro. The CD33(pos) cell lines HL60, OCI/AML2, and OCI/AML5 showed decreased proliferation when exposed to immunotoxin for 24-72 h. The CD33(neg) cell line OCI/AML3 was relatively resistant to HuM195, and all cell lines were resistant to equimolar concentrations of unconjugated antibody and gelonin. Primary blast cultures from seven patients with AML had CD33 detectable on 75.7-99.8% of cells by flow cytometry, and all showed dose-dependent decreases in clonogenic cell survival during 24-h incubation with the immunotoxin. Cells selected for low CD33 expression by cell sorting or by prolonged incubation with immunotoxin could reexpress CD33 at baseline levels and remained sensitive to immunotoxin. We conclude that humanized M195 conjugated to recombinant gelonin has antileukemic activity and should be considered for clinical testing in Phase I trials.

UR - http://www.scopus.com/inward/record.url?scp=0031850006&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031850006&partnerID=8YFLogxK

M3 - Article

C2 - 9717827

AN - SCOPUS:0031850006

VL - 4

SP - 1971

EP - 1976

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 8

ER -