Monoclonal Antibody and Peptide-Targeted Radiotherapy of Cancer

MONOCLONAL ANTIBODY AND PEPTIDE-TARGETED RADIOTHERAPY OF CANCER......Page 4
CONTENTS......Page 10
Preface......Page 20
Contributors......Page 24
1.1 Introduction......Page 28
1.2 Intact Murine Monoclonal Antibodies......Page 29
1.3 Recombinant Immunoglobulin Molecules......Page 31
1.3.1 Chimeric Monoclonal Antibodies......Page 32
1.3.2 Humanized Monoclonal Antibodies......Page 33
1.3.3 Human Monoclonal Antibodies......Page 36
1.4 Nanobodies......Page 37
1.5 Domain-Deleted Monoclonal Antibodies......Page 39
1.6 Hypervariable Domain Region Peptides......Page 40
1.7 Fv Fragments......Page 41
1.7.1 Multimeric Fv Forms......Page 43
1.8 Minibodies......Page 46
1.10 Affibodies......Page 48
1.11.1 Fc Domain and the Neonatal Fc Receptor......Page 50
1.11.2 PEGylation......Page 52
1.11.3 Albumin Binding......Page 53
References......Page 55
2.1 Introduction......Page 66
2.2 Tumor and Normal Tissue Uptake of Monoclonal Antibodies and Peptides......Page 67
2.3 Selection of a Radionuclide for Tumor Imaging......Page 68
2.4 Selection of a Radionuclide for Targeted Radiotherapy......Page 71
2.5.1 Iodine Radionuclides......Page 74
2.5.2 Bromine Radionuclides......Page 78
2.5.3 Fluorine Radionuclides......Page 80
2.5.4 Astatine Radionuclides......Page 83
2.6.1 Technetium Radionuclides......Page 84
2.6.2 Rhenium Radionuclides......Page 89
2.6.3 Indium Radionuclides......Page 90
2.6.4 Yttrium Radionuclides......Page 96
2.6.5 Gallium Radionuclides......Page 98
2.6.6 Copper Radionuclides......Page 99
2.6.8 Lead, Bismuth, and Actinium Radionuclides......Page 101
2.7.1 Evaluation of the Homogeneity of Radiolabeled mAbs and Peptides......Page 102
2.7.2 Measurement of Radiochemical Purity......Page 104
2.7.3 Measurement of Immunoreactivity/Receptor Binding Properties......Page 105
2.7.4 Evaluation of In Vitro and In Vivo Stability......Page 107
2.7.6 Preclinical Studies to Evaluate Antitumor Effects and Normal Tissue Toxicity......Page 108
2.8 Summary......Page 109
References......Page 110
3.2 Peptide Targets......Page 128
3.3 Peptides as Cancer Targeting Agents......Page 129
3.3.1 Discovery of Novel Cancer Binding Peptides......Page 131
3.3.2 The Addition of a Radionuclide to a Peptide......Page 135
3.3.3 Improving the In Vivo Behavior of Peptides......Page 140
3.4 Multimodality Agents......Page 141
References......Page 142
4.1 Introduction......Page 148
4.2 Radiotherapy with (111)In-Octreotide......Page 149
4.3 Radiotherapy with (90)Y-DOTATOC......Page 150
4.4 Targeted Radiotherapy Studies with (177)Lu-Octreotate......Page 151
4.5 PRRT with Other Somatostatin Analogues......Page 155
4.7 Comparison with Chemotherapy......Page 156
4.8 Options for Improving PRRT and Future Directions......Page 157
References......Page 160
5.1 Malignant Brain Tumors......Page 166
5.2 Rationale for Locoregional Therapy......Page 167
5.3 Targeted Radiotherapy of Brain Tumors......Page 168
5.4 Rationale for Tenascin-C as a Target for Radionuclide Therapy......Page 169
5.4.1 Tenascin-C Targeting Vehicles......Page 170
5.4.2 BC-2 and BC-4 mAbs: The Italian Experience......Page 171
5.4.3 Antitenascin-C mAb 81C6: The Duke Experience......Page 173
5.4.4 Strategies for Improving the Efficacy of 81C6-Based Targeted Radiotherapy......Page 177
5.4.5 Evaluation of More Stable Constructs: Human/Mouse Chimeric 81C6......Page 179
5.4.6 Evaluation of More Potent Radionuclides: Astatine-211-Labeled CH81C6......Page 181
5.4.7 Pretargeted Radioimmunotherapy......Page 182
5.4.8 Receptor-Targeted Peptides......Page 183
5.4.9 Chlorotoxin......Page 184
5.5 Perspective for the Future......Page 185
References......Page 186
6.1 Introduction......Page 196
6.2.1 Historical Background of RIT......Page 197
6.2.2 Radionuclides Used in RIT......Page 198
6.2.3 Administration of RIT: General Principles and Practice......Page 200
6.2.4 Characteristics of Radiolabeled Monoclonal Antibodies to CD20......Page 202
6.2.5 Clinical Results of Anti-CD20 RIT for Relapsed NHL......Page 206
6.2.6 Safety of Bexxar RIT......Page 212
6.3.1 Radiolabeled Epratuzumab......Page 214
6.4 RIT Versus Immunotherapy......Page 215
6.5 RIT in Rituximab Refractory Patients......Page 216
6.6 RIT for Previously Untreated Patients......Page 217
6.7 RIT for Relapsed Large-Cell Lymphoma......Page 218
6.9 RIT for Mantle Cell Lymphoma......Page 219
6.11 Risk of Myelodysplasia with RIT......Page 220
6.12 Feasibility of Treatment After RIT Failure......Page 221
6.13 Combinations of RIT and Chemotherapy......Page 222
6.14 High-Dose RIT with Stem Cell Support......Page 224
6.14.1 Use of RIT After Stem Cell Transplantation......Page 226
6.16 Retreatment with RIT......Page 227
6.18 RIT in Patients with Lung Involvement......Page 228
6.21 RIT in Older Patients......Page 229
6.25 Summary......Page 230
6.26 Future Directions......Page 231
References......Page 232
7.1 Introduction......Page 246
7.3 Radionuclide Selection......Page 247
7.4 Radiolabeling......Page 249
7.5 Pharmacokinetics and Dosimetry......Page 252
7.5.1 Pretargeted Approaches......Page 253
7.6.1 (131)I-M195 and (131)I-Lintuzumab......Page 254
7.6.4 (131)I-Labeled BC8......Page 257
7.6.5 (188)Re-Anti-CD66......Page 258
7.7.2 (213)Bi-Lintuzumab......Page 259
7.7.3 (225)Ac-Lintuzumab......Page 260
References......Page 261
8.1 Introduction......Page 268
8.2 The Challenge of Improving Tumor/Nontumor Ratios......Page 270
8.3.1 Bispecific Antibodies and Radiolabeled Haptens......Page 273
8.3.2 Pretargeting: Development of Avidin/Streptavidin and Radiolabeled Biotin......Page 277
8.3.3 Pretargeting with Oligonucleotide/Complementary Oligonucleotide Immunoconjugates......Page 278
8.3.4 Core Principles Associated with Pretargeting Procedures......Page 279
8.4.1 “Two-Step” Pretargeting with Streptavidin Immunoconjugates and (90)Y-Biotin......Page 287
8.4.2 “Three-Step” Pretargeting with Streptavidin Immunoconjugates and (90)Y-Biotin......Page 290
8.4.3 Bispecific Antibody-(131)I-Hapten-Peptide......Page 293
8.5 Prospects for Combination Therapies......Page 295
8.6 Future Innovations......Page 297
References......Page 301
9.1 Introduction......Page 316
9.2 Radiobiological Effects of Auger Electrons......Page 317
9.2.1 Relative Biological Effectiveness......Page 318
9.2.2 DNA Damage......Page 319
9.2.3 Bystander Effects......Page 320
9.3 Selection of an Auger Electron-Emitting Radionuclide......Page 321
9.4 Microdosimetry......Page 323
9.4.1 The “Cross-Dose” Contribution......Page 325
9.5.1 DNA Synthesis Pathways as a Target......Page 326
9.5.2 Somatostatin Receptors......Page 327
9.5.3 Epidermal Growth Factor Receptors......Page 337
9.5.4 Targeting HER2 Receptors......Page 345
9.5.5 Other Antigens/Receptors in Solid Tumors......Page 348
9.5.6 Cell-Surface Epitopes in Lymphomas......Page 351
9.5.7 Targeting CD33 Epitopes in Acute Myeloid Leukemia......Page 354
9.6.1 Radiolabeled Estradiol Analogues......Page 356
9.6.2 Radiolabeled mIBG Analogues......Page 357
9.6.3 DNA Intercalating Agents......Page 358
9.7 Summary and Conclusions......Page 359
References......Page 360
10.1 Introduction......Page 376
10.2.2 Replicating Viruses: Mechanism of Tumor Cell Specificity......Page 379
10.3.1 Somatostatin Receptor......Page 381
10.3.2 Sodium Iodide Symporter......Page 390
10.3.3 Other Receptors......Page 402
10.4 Combined Oncolytic and Targeted Radiotherapy......Page 408
References......Page 409
11.1 Introduction......Page 424
11.2 Traditional Approaches to Preclinical Evaluation of Radiotherapeutics......Page 426
11.3 Models of Cancer......Page 429
11.3.1 Cancer as a Complex Collection of Neoplastic Diseases......Page 430
11.3.2 Human Breast Cancer Cell Culture Models......Page 431
11.3.3 Animal Models......Page 432
11.4 Animal Models for Evaluating Radiopharmaceuticals: Unresolved Issues and Challenges for Translation......Page 434
References......Page 437
12.1 Introduction......Page 446
12.2 Targeted Radionuclide Therapy: Concepts......Page 447
12.3 Radiation-Induced DNA Damage......Page 448
12.4 Cellular DNA Damage Surveillance–Response Networks......Page 449
12.5 Mammalian DNA-Repair Pathways......Page 452
12.5.1 The BER Pathway......Page 453
12.5.2 DSB-Repair Pathways......Page 454
12.6.1 Apoptosis......Page 455
12.6.2 Necrosis......Page 456
12.6.5 Mitotic Catastrophe......Page 457
12.7 Conventional Models for Cell Survival Curves, Fractionation, and Dose-Rate Effects......Page 458
12.8.1 Phenomenology of HRS-IRR......Page 460
12.8.2 Mechanistic Basis of HRS-IRR......Page 462
12.8.3 Ultrafractionation......Page 472
12.9 Inverse Dose-Rate Effects......Page 474
12.10 Cross fire......Page 478
12.11 The Radiobiological Bystander Effect......Page 479
12.12 The Adaptive Response......Page 480
12.13 A Possible Contribution from Low-Dose Radiobiological Mechanisms to TRT Tumor Responses?......Page 482
12.14 Use of Radionuclides Other Than β-Particle Emitters......Page 483
12.15 Role of Tumor Hypoxia and Fractionation Effects......Page 484
References......Page 485
13.1 Introduction......Page 500
13.2.1 MIRD Equations......Page 502
13.2.3 Radionuclide Data......Page 503
13.3.1 Data Collection......Page 504
13.3.2 Preclinical Macrodosimetry......Page 506
13.3.3 Nonuniform Distribution and Multicellular Dosimetry......Page 507
13.4.1 Planar Conjugate View Imaging......Page 508
13.4.2 Accounting for Scatter Effects in SPECT and Planar Quantification......Page 510
13.4.3 3D CT/Spect/Planar Hybrid Methods......Page 512
13.5 Dosimetry for Dose-Limiting Organs and Tumors......Page 514
13.5.1 Marrow Dosimetry......Page 515
13.5.2 Other Normal Organ Toxicity......Page 518
13.5.3 Tumor Dosimetry......Page 519
13.6 Conclusions......Page 522
References......Page 523
14.1 Introduction......Page 534
14.2 Historical Review of Bystander Effects in the Context of Radiation Damage to Cells......Page 535
14.3 New Knowledge and the Pillars of the Developing New Paradigm......Page 536
14.3.1 Key Points and Historical Time Line......Page 537
14.5 The New Meaning of the LNT Model......Page 540
14.6.1 Emerging Biomarkers of Nontargeted Radiation Effects......Page 541
14.7 Bystander Phenomena in Targeted and Conventional Radiotherapy......Page 542
14.8. Mechanisms Underlying Bystander Effects and Detection Techniques......Page 545
14.9. The Future......Page 547
References......Page 548
15.1 Introduction......Page 554
15.2.1 Background and Basic Principles......Page 555
15.2.2 PET Radiotracers......Page 556
15.2.3 PET and PET/CT Imaging of Biologic Features of Cancer......Page 557
15.3.1 Conventional Methods Used to Evaluate Treatment Response......Page 560
15.3.2 Molecular Imaging for Monitoring Treatment Response......Page 561
References......Page 566
16.1 Introduction......Page 570
16.2 Applying Economics in Theory......Page 571
16.2.1 A Simple Constrained Optimization Problem......Page 572
16.3.1 How are Economic Evaluations Used to Make Decisions in Practice?......Page 579
16.3.2 Challenges and Concerns......Page 581
16.3.3 How Does the Model Affect the Results?......Page 584
16.4.1 What has been Published about the Cost-Effectiveness of Zevalin?......Page 586
16.4.2 Why the Scottish Medicines Consortium Said “No” (Again)......Page 590
16.5 Conclusions......Page 591
References......Page 592
17.1 Introduction......Page 598
17.2 Administrative and Organizational Elements......Page 600
17.3 Pharmaceutical Quality Elements......Page 602
17.3.1 Tumor Targeting Component......Page 604
17.3.2 Radionuclide Binding Component......Page 610
17.3.3 Radionuclide Component......Page 612
17.3.4 Drug Product......Page 614
17.4 Nonclinical Study Elements......Page 620
17.4.1 (Radio)pharmacology Studies......Page 622
17.4.2 Safety Pharmacology Studies......Page 624
17.4.3 Toxicology Studies......Page 625
17.5 Clinical Study Elements......Page 628
17.5.1 Pre-Phase 1 and Exploratory Phase 1 Clinical Investigations......Page 629
17.5.2 Traditional Phase 1 to Phase 3 Clinical Trials......Page 632
17.6 Summary......Page 634
References......Page 635
Index......Page 640