Chimeric Toxins: Mechanisms of Action and Therapeutic Applications (Cellular and Molecular Mechanisms of Toxic Action)

288 Pages·2002·1.35 MB·English

by  Haya Lorberboum-Galski

Chimeric Toxins
Cellular and molecular mechanisms of toxin action
Edited by Philip Lazarovici
The Hebrew University of Jerusalem, Israel
A series of books on various aspects of toxin research, giving a broader emphasis on the
mechanism of action, structure–function relationship, the use of toxins as research tools
and their therapeutic applications.
Volume 1
Toxins and signal transduction
Y. Gutman and P. Lazarovici
Volume 2
Secretory systems and toxins
M. Linial, A. Grasso and P. Lazarovici
Volume 3
Site-selective neurotoxicity
D. Lester, W. Slikker Jr. and P. Lazarovici
Volume 4
Chimeric toxins
H. Lorberboum-Galski and P. Lazarovici
Chimeric Toxins
Mechanisms of Action and Therapeutic
Applications
Edited by
Haya Lorberboum-Galski
and Philip Lazarovici
London and New York
First published 2002
By Taylor & Francis
11 New Fetter Lane, London EC4P 4EE
Simultaneously published in the USA and Canada
by Taylor & Francis Inc,
29 West 35th Street, New York, NY 10001
Taylor & Francis is an imprint of the Taylor & Francis Group
This edition published in the Taylor & Francis e-Library, 2003.
© 2002 Taylor & Francis
All rights reserved. No part of this book may be reprinted or reproduced
or utilized in any form or by any electronic, mechanical, or other means,
now known or hereafter invented, including photocopying and recording,
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is true and accurate at the time of going to press. However, neither the publisher
nor the authors can accept any legal responsibility or liability for any errors or
omissions that may be made. In the case of drug administration, any medical
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strongly advised to consult the manufacturer’s guidelines.
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ISBN 0-203-21647-4 Master e-book ISBN
ISBN 0-203-27266-8 (Adobe eReader Format)
ISBN 0-415-28386-8 (Print Edition)
Contents
List of figures vii
List of tables ix
List of contributors xi
Preface to the series xiii
Preface xv
1 Bacterial and plant toxins – general mode of action 1
A.E. FRANKEL ANDP.D. HALL
2 Diphtheria toxin – structure, function, and its clinical applications 14
R.C. RATTS ANDJ.C. VANDERSPEK
3 Ricin A: structure, function and its clinical applications 37
M. COLOMBATTI
4 Pathways of delivering toxins into the cytosol of target cells 86
J. M. LORD, P.J. DAY, M.E. JACKSON, S.R. OWENS, J.C. SIMPSON,
D.C. SMITH ANDL.M. ROBERTS
5 Engineering immunotoxins for improving their therapeutic activity 99
C. COHEN, G. DENKBERG, M. EPEL ANDY. REITER
6 Ligand–receptor interactions studied with chimeric proteins 135
H. LORBERBOUM-GALSKI
7 Chimeric proteins: a novel approach for eliminating specific cell
populations for targeted human therapy 148
A. BEN-YEHUDAH, R. BELOSTOTSKY, R. AQEILAN, Y. AZAR,
I. STEINBERGER, A. FISHMAN, A. NECHUSHTAN, S. YARKONI AND
H. LORBERBOUM-GALSKI
8 Chimeric neurotoxins – a molecular neurosurgery approach 168
P. LAZAROVICI
9 Targeted immunotherapy of autoimmune diseases by chimeric toxins 179
B.A. HOLDER ANDJ.G. KRUEGER
vi Contents
10 Immunotoxins for targeted cancer therapy 203
R.J. KREITMAN
11 Molecular targeting of brain tumors with cytotoxins:
novel bacterial toxin-containing anti-brain tumor therapeutics 222
W. DEBINSKI
12 Toxin in the development of vaccines 247
C.-T. HSU, C.-Y. TING ANDJ. HWANG
Index 261
Figures
1.1 The (cid:2)carbon backbone of DT 2
1.2 Model of cell intoxication by diphtheria toxin 3
1.3 The (cid:2)carbon backbone of PE 4
1.4 Model of cell intoxication by Pseudomonas exotoxin 5
1.5 The (cid:2)carbon backbone of ricin 6
1.6 Model of cell intoxication by ricin 7
2.1 Schematic representation of DT Fragments A and B 15
4.1 Schematic representations of protein toxin structure 87
4.2 Proposed route of cell entry for protein toxins 94
5.1 Immunotoxins: first-generation conjugates and second-generation
recombinant molecules 102
5.2 Recombinant immunotoxins: design, cloning, construction, and
composition of scFv- and dsFv-immunotoxins 104
5.3 Recombinant Fv fragments 106
5.4 Recombinant scFv-immunotoxin 107
5.5 The mode of action of Pseudomonas Exotoxin A 110
6.1 IL2R (cid:2),(cid:3)and (cid:4)subunits gene expression in human B-cell lines
analyzed by PCR 137
6.2 Cytotoxic activity of IL2-PE664Gluon human B-cell lines 140
6.3 Cytotoxic activity of MBP-PE40 chimeric proteins against anti-MBP
T-cell lines 143
6.4 Effect of the partially purified GnRH-PE66 on various cell lines 144
7.1 Mode of action of chimeric proteins 149
7.2 Structure of PE and its modified forms 149
7.3 Effect of MBP-PE on rat K1a anti-MBP-T cells 151
40
7.4 Effect of MBP-PE on EAE in SJL mice 153
40
7.5 Cytotoxic activity of various chimeric proteins against MC-9 cells 154
7.6 Inhibition of the PCA reaction in mice treated with Fc2(cid:2)-3-PE40 156
7.7 The Effect of Fc2(cid:2)-3-PE40 on seratonin release from C57 cells 157
7.8 Effect of partially purified GnRH-PE on various primary cultures 160
66
7.9 Effect of L-GnRH-PE on average tumor size (colon carcinoma) in
66
nude mice 161
9.1 A variety of fusion toxins, chimeric toxins and other chimeric proteins 187
10.1 Schematic structure of immunotoxins 207
11.1 Schematic drawing of two bacterial toxins, PE A and DT 226
11.2 Schema of a recombinant cytotoxin targeted to cancer cells 227
viii List of figures
11.3 Schematic drawing of interleukin 13 (IL13)-based cytotoxins
containing derivatives of either PE or DT 231
11.4 Autoradiography of thebinding of 125I-IL13.E13K-PE38QQR
cytotoxin to a GBM specimen 232
11.5 Northern blot analysis of human IL13R(cid:2)2 transcripts,
human IL4 R(cid:3)and that of action in normal human organs 235
11.6 Bottom view of thepredicted three-dimensional structure of
human IL 13, as visualized using WebLab ViewerPro 237
12.1 PE and modified PEs with sequential deletion at carboxyl-terminal 249
12.2 Effects of vaccination with PEIF, OprF, and nontoxic PE 253
12.2 Degeneration of the ovaries of rabbits immunized with PEIa-GnRH12 255
Color Plates
I The (cid:2)carbon backbone of DT
(See Chapter 1, p. 2. Arthur E. Frankel and Philip D. Hall)
II Model of cell intoxication by diphtheria toxin
(See Chapter 1, p. 3. Arthur E. Frankel and Philip D. Hall)
III The (cid:2)carbon backbone of PE
(See Chapter 1, p. 4. Arthur E. Frankel and Philip D. Hall)
IV Model of cell intoxication by Pseudomonas exotoxin
(See Chapter 1, p. 5. Arthur E. Frankel and Philip D. Hall)
V The (cid:2)carbon backbone of ricin
(See Chapter 1, p. 6. Arthur E. Frankel and Philip D. Hall)
VI Model of cell intoxication by ricin
(See Chapter 1, p. 7. Arthur E. Frankel and Philip D. Hall)
VII Recombinant Fv fragments
(See Chapter 5, p. 106. Yoram Reiter et al.)
VIII Recombinant scFv-immunotoxin
(See Chapter 5, p. 107. Yoram Reiter et al.)
IX Bottom view of thepredicted three-dimensional structure of human IL13, as
visualized using WebLab ViewerPro
(See Chapter 11, p. 237. Waldemar Debinski)
Tables
1.1 Mechanisms of cell resistance to DT chimeric proteins 3
1.2 Mechanisms of resistance to PE hybrid proteins 5
1.3 Cellular phenotypes for ricin toxin resistance 8
2.1 Current and potential therapeutic applications of diphtheria-based
fusion protein toxins 16
5.1 Examples of recombinant immunotoxins against cancer 100
5.2 Examples for improving recombinant immunotoxins by
antibody engineering 114
6.1 Expression of the (cid:2), (cid:3), (cid:4)IL2R-subunits in the various B-cell lines,
determined by PCR analysis 138
6.2 Effect of IL2-PE664Gluon B-cell lines representing different
stages of B-cell lineage ontogeny 139
6.3 Comparison of binding affinities, activation and ID values for
50
DAB IL2 and its variant mutated chimeras 141
389
7.1A Effect of MBP-PE on EAE in SJL mice 152
40
7.1B Reversal of EAE by MBP-PE after the appearance of
40
the clinicaldisease 153
7.2 Inhibition of the PCA reaction in mice treated with Fc2(cid:2)-3-PE40
for 7 days 155
7.3 Effect of GnRH-PE and L-GnRH-PE on various cell lines 159
66 66
8.1 Suicide transport toxins, immunolesioning-chimeric toxins and
nocitoxins 170
9.1 Fusion toxins 182
9.2 Chimeric toxins 184
9.3 Other engineered immune modulators (potentially toxic) 185
10.1 Results of recent clinical trials of chimeric toxins against cancer 205
11.1 A list of third generation of IL13 multiple mutant-based,
PE38QQR- or PE1E-containing cytotoxins 239
12.1 Toxicity of PE((cid:4)576–613) in 5- and 9-week-old ICR mice 250
12.2 Active immunization against PE intoxication in ICR mice
preimmunized with different doses of PE((cid:4)576–613) 251
12.3 Opsonophagocytosis of different strains of P. aeruginosaby murine
peritoneal macrophages 252