Cytotoxins and immunotoxins for cancer therapy: clinical applications

Book Cover......Page 1
Title......Page 2
Copyright......Page 3
Preface......Page 4
About the Editors......Page 7
Contributors......Page 9
Contents......Page 12
part one Pseudomonas exotoxin-based immunotoxins/cytotoxins......Page 14
chapter one Targeting of Pseudomonas exotoxin-based immunotoxins to hematologic malignancies......Page 16
Immunotoxins in the hierarchy of surface-targeted therapies for hematologic malignancies......Page 17
Structure and function of PE-based toxins......Page 18
Fragments of PE used for connecting to ligands......Page 19
Early immunotoxins targeting CD25......Page 20
Recombinant immunotoxins targeting CD25......Page 21
Clinical activity of LMB-2 in patients with CD25+ malignancies......Page 22
PE-based toxins targeting CD22......Page 23
Activity of BL22 in patients with cladribine-resistant HCL......Page 24
Improved form of BL22......Page 25
Conclusions......Page 26
References......Page 27
chapter two Interleukin-4-targeted cytotoxin for recurrent glioblastoma therapy......Page 36
Expression and structure of IL-4R on human brain tumor cell lines......Page 37
Development of IL-4R-targeted cytotoxin (in vitro studies)......Page 40
In vivo antitumor activity of IL-4 cytotoxin in animal models of glioblastoma......Page 43
Toxicology and pharmacokinetics of IL-4 cytotoxin in preclinical studies......Page 44
Clinical trials with IL-4 cytotoxin in recurrent glioblastoma patients......Page 45
Concluding remarks......Page 48
References......Page 49
chapter three Interleukin-13 receptors and development of IL-13-Pseudomonas exotoxin for human cancer therapy......Page 58
Introduction......Page 59
IL-13 and its receptors......Page 61
Signal transduction through IL-13 receptors......Page 63
Development of IL-13 Pseudomonas exotoxin (IL-13-PE38QQR) to target IL-13 receptor positive tumor cells......Page 64
IL-13Rα2 chain is primarily responsible for IL-13 cytotoxin-mediated cytotoxicity......Page 66
Targeting IL-13R for malignant brain tumor and RCC therapy......Page 67
Toxicity and Pharmacokinetic studies......Page 68
Clinical studies......Page 69
Conclusions and future directions......Page 72
Bibliography......Page 73
part two Ricin-based immunotoxins/cytotoxins......Page 84
chapter four Ricin immunotoxins in lymphomas: Clinical application......Page 86
Background......Page 87
Ricin A-chain ITs......Page 88
Blocked ricin ITs......Page 89
Ricin A-chain ITs in NHL against CD22......Page 90
Ricin A-chain ITs in NHL against CD19......Page 92
Ricin A-chain IT cocktail in NHL......Page 93
Blocked ricin ITs in NHL......Page 94
Ricin A-chain ITs against CD25......Page 97
Ricin A-chain ITs against CD30......Page 98
Vascular leak syndrome......Page 100
Summary and perspectives......Page 101
References......Page 102
part three Diphtheria toxin-based immunotoxins/cytotoxins......Page 108
Introduction......Page 110
IL-13 receptor......Page 114
uPA receptor......Page 115
DTIL13 efficacy......Page 116
DTAT efficacy......Page 118
Does DTAT have an advantage over DTIL13?......Page 120
References......Page 121
chapter six DAB389IL-2 (Ontak™): Development and therapeutic applications......Page 128
IL-2 receptor expression......Page 129
Early clinical studies of DAB486IL-2......Page 130
Development of DAB389IL-2......Page 132
Clinical studies with DAB389IL-2......Page 133
Phase III pivotal study of DAB389IL-2 in CTCL......Page 135
Soluble IL-2R......Page 138
DAB389IL-2 in combination with other agents......Page 139
DAB389IL-2 in the treatment of other lymphoid malignancies......Page 140
Immune-mediated diseases......Page 141
References......Page 142
Introduction......Page 146
Targeted protein toxins......Page 147
Preclinical studies......Page 148
Drug delivery......Page 149
Phase I clinical study......Page 150
Phase II clinical study......Page 153
Conclusions and future directions......Page 156
References......Page 157
Introduction......Page 160
AML......Page 161
DT fusion proteins......Page 162
DT388GMCSF......Page 163
Preclinical studies with DT388GMCSF......Page 164
Clinical studies with DT388GMCSF......Page 166
References......Page 175
Introduction......Page 182
VEGF-toxin conjugates......Page 185
Inhibition of endothelial cell proliferation and angiogenesis......Page 187
Inhibition of tumor growth by VEGF-DT toxin conjugates......Page 190
Problems and prospects......Page 191
References......Page 192
part four Miscellaneous......Page 196
Introduction......Page 198
cBR96-doxorubicin (SGN-15)......Page 199
Phase I studies of SGN-15......Page 201
Phase II studies of SGN-15 in breast cancer......Page 202
In vitro activity of SGN-15 in combination with chemotherapy......Page 203
Phase II study of SGN-15 with docetaxel in metastatic breast cancer......Page 204
References......Page 205
chapter eleven Anti-CD33 calicheamicin immunoconjugate therapy of acute myeloid leukemia......Page 208
Acute myeloid leukemia......Page 209
Antibodies in the therapy of AML......Page 210
The development of gemtuzumab ozogamicin......Page 211
Efficacy......Page 212
Older patients......Page 215
Veno-occlusive disease......Page 216
Relapsed/refractory disease......Page 217
Multidrug resistance phenotype......Page 218
Future directions......Page 219
References......Page 220
Index......Page 230