Drug Targeting Organ-Specific Strategies

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XXII Contents 8.5.1.5 Monoclonal Antibody–Drug Conjugates . . . . . . . . . . . 213 8.5.1.6 Radioimmunoconjugates . . . . . . . . . . . . . . . . . . . 215 8.5.2 Bispecific Monoclonal Antibodies . . . . . . . . . . . . . . . . . . . . 215 8.5.3 Pro-drug Strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 8.5.3.1 Antibody-directed Enzyme Pro-drug Therapy (ADEPT) . 217 8.5.3.2 Pro-drug Monotherapy . . . . . . . . . . . . . . . . . . . . 217 8.5.4 (Synthetic) (co)Polymers . . . . . . . . . . . . . . . . . . . . . . . . . 218 8.5.5 Liposomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 8.6 Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221 8.6.1 MAb and MAb-based Constructs . . . . . . . . . . . . . . . . . . . . 221 8.6.2 Pro-drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224 8.6.3 (Synthetic) (co)Polymers . . . . . . . . . . . . . . . . . . . . . . . . . 225 8.6.4 Liposomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 8.7 Animal Models: their Predictive Value . . . . . . . . . . . . . . . . . . . . . . 226 8.8 Conclusions and Future Perspectives . . . . . . . . . . . . . . . . . . . . . . . 226 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 9 Tumour Vasculature Targeting Daisy W. J. van der Schaft, S. Ramakrishnan, Grietje Molema, Arjan W. Griffioen 233 9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 9.1.1 Functions of Vascular Endothelial Cells in the Body . . . . . . . . . . 234 9.1.2 Molecular Control of Tumour Growth-related Angiogenesis . . . . . 234 9.1.2.1 Role of Growth Factors VEGF and FGF-2 . . . . . . . . . 235 9.1.2.2 Role of Integrins . . . . . . . . . . . . . . . . . . . . . . . . 236 9.1.2.3 Role of the Extracellular Matrix . . . . . . . . . . . . . . . 236 9.1.2.4 Role of Subendothelial Support Cells . . . . . . . . . . . . 236 9.2 Angiogenesis Assays and Models . . . . . . . . . . . . . . . . . . . . . . . . . 237 9.2.1 Endothelial Cell Sources . . . . . . . . . . . . . . . . . . . . . . . . . 237 9.2.2 Functional Assays with Endothelial Cells . . . . . . . . . . . . . . . . 238 9.2.2.1 Cell Growth Assays . . . . . . . . . . . . . . . . . . . . . . 238 9.2.2.2 Adhesion and Migration Assays . . . . . . . . . . . . . . . 239 9.2.3 In Vitro Angiogenesis Assays . . . . . . . . . . . . . . . . . . . . . . . 239 9.2.4 In Vivo Assays to Study Angiogenesis and Targeting of Angiogenic Blood Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240 9.3 Tumour Vasculature Targeting and Pre-clinical Experience . . . . . . . . . . 241 9.3.1 Growth Factor Receptor Targeting . . . . . . . . . . . . . . . . . . . 243 9.3.1.1 VEGF Receptor Targeting . . . . . . . . . . . . . . . . . . . 243 9.3.1.2 Other Growth Factor Receptors Used for Targeting Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245 9.3.2 Endoglin Targeting . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245 9.3.3 Targeting Integrins to Tumour Vasculature . . . . . . . . . . . . . . . 246 9.3.4 Tumour Vasculature-specific Blood Coagulation Induction . . . . . . 247 9.3.5 Other Potential Targets . . . . . . . . . . . . . . . . . . . . . . . . . . 249
Contents XXIII 9.4 Tumour Vasculature targeting Potentials: Extrapolation of Animal Studies to the Human Situation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250 9.5 Summary and Future Perspectives . . . . . . . . . . . . . . . . . . . . . . . . 251 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 10 Phage Display Technology for Target Discovery in Drug Delivery Research Ricardo Mutuberria, Jan-Willem Arends, Arjan W. Griffioen, Hennie R. Hoogenboom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255 10.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255 10.2 Phage Display Technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255 10.2.1 Introduction to the Technology . . . . . . . . . . . . . . . . . . . . . 255 10.2.2 Phage Display Libraries . . . . . . . . . . . . . . . . . . . . . . . . . 258 10.2.2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 258 10.2.2.2 Peptide Display . . . . . . . . . . . . . . . . . . . . . . . . . 259 10.2.2.3 Antibody Display . . . . . . . . . . . . . . . . . . . . . . . . 260 10.2.2.4 Protein Scaffolds . . . . . . . . . . . . . . . . . . . . . . . . 261 10.2.2.5 Engineering Proteins with Phage Libraries . . . . . . . . . 262 10.2.2.6 cDNA Expression Libraries . . . . . . . . . . . . . . . . . . 262 10.3 Generation of Ligands Amenable for Targeting . . . . . . . . . . . . . . . . . 263 10.3.1 Selection of Ligands to Defined Targets . . . . . . . . . . . . . . . . . 263 10.3.2 Phage Display for Target Identification . . . . . . . . . . . . . . . . . 264 10.3.2.1 In Vitro Selections on Complex Antigens . . . . . . . . . . 264 10.3.2.2 In Vivo Selections and Selections for Functional Activity . 266 10.4 Engineering and Optimization for Targeting . . . . . . . . . . . . . . . . . . . 266 10.5 Discovery of Novel Therapeutics Using Phage Display Technology . . . . . . 268 10.6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270 11 Development of Proteinaceous Drug Targeting Constructs Using Chemical and Recombinant DNA Approaches Robbert J. Kok, Sigridur A. Ásgeirsdóttir, Willem R. Verweij . . . . . . . . . . 275 11.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 11.2 The Carrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276 11.2.1 Albumin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277 11.2.2 Low Molecular Weight Proteins . . . . . . . . . . . . . . . . . . . . . 277 11.2.3 Monoclonal Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . 278 11.2.4 Transferrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278 11.3 The Homing Device . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 11.3.1 Carbohydrate Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . 280 11.3.2 Folate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 11.3.3 Peptide Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
Page 1 and 2: Drug Targeting Organ-Specific Strat
Page 5 and 6: Preface Drug Targeting Organ-Specif
Page 7 and 8: Foreword Drug Targeting Organ-Speci
Page 9 and 10: X List of Contributors Henderik W.
Page 11 and 12: XII List of Contributors Grietje Mo
Page 13 and 14: Contents Drug Targeting Organ-Speci
Page 15 and 16: Contents XVII 3 Pulmonary Drug Deli
Page 17 and 18: Contents XIX 5.2.1.6 Identification
Page 19: Contents XXI 7.5 In Vitro Technique
Page 23 and 24: Contents XXV 12.8. Tissue Slices fr
Page 27 and 28: Dexa dexamethasone DIVEMA divinyl e
Page 29 and 30: LRP lung resistance related protein
Page 31 and 32: ROS reactive oxygen species RSV res
Page 33 and 34: Index a ADEPT 217, 224, 268, 291 ad
Page 35 and 36: e E. coli expression system 292 eff
Page 37 and 38: polymers, soluble 4, 218 - dendrime
Page 39 and 40: 2 1 Drug Targeting: Basic Concepts
Page 61 and 62: 24 2 Brain-Specific Drug Targeting
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34 2 Brain-Specific Drug Targeting
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54 3 Pulmonary Drug Delivery: Deliv
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4 Cell Specific Delivery of Anti-In
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The sinusoids are lined by the disc
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4.2.2.2 Phagocytosis and Transcytos
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ther inflammatory cells or accessor
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4.3 Hepatic Inflammation and Fibros
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process is not yet available. Sever
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this carrier to the KCs.When the ma
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e taken up rapidly by mannose recep
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y the transcriptional regulatory pr
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4.8 Testing Liver Targeting Prepara
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4.8 Testing Liver Targeting Prepara
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4.9 Targeting of Anti-inflammatory
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4.9 Targeting of Anti-inflammatory
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with monoclonal and bispecific anti
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References 117 [50] Coleman DL, Eur
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References 119 [133] Cronstein BN,
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5 Delivery of Drugs and Antisense O
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5.1 Introduction 123 convoluted tub
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treatment of the targeted cell and
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CL uptake (ml/min/g) centration pro
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5.2.1.4 Specific Binding of Alkylgl
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5.2 Renal Delivery Using Pro-Drugs
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5.2 Renal Delivery Using Pro-Drugs
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5.3 Renal Delivery Using Macromolec
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5.4 Renal Delivary of Antisense Oli
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5.4 Renal Delivery of Antisense Oli
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5.4.8 Benefits and Limitations of A
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via reabsorption from the luminal s
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References 153 [66] Franssen EJF, M
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References 155 [145] Van Zwieten PA
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158 6 A Practical Approach in the D
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172 7 Vascular Endothelium in Infla
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8 Strategies for Specific Drug Targ
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8.2.2 Histogenesis The traditional
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may become obstructed and compresse
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8.5 Strategies to Deliver Drugs to
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8.5 Strategies to Deliver Drugs to
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larly cytotoxic immune effector cel
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contributes to limited tumour penet
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ples onto anti-EGP-2 scFv. Biologic
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In the case of drug-monoclonal anti
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cells, the presence of co-stimulato
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Monomethoxy-polyethylene glycol CH
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e efficiently loaded into the lipos
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8.6 Clinical Studies 223 Table 8.5.
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8.6.3 (Synthetic) (co)Polymers Solu
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8.8 Conclusions and Future Perspect
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References 229 [43] Chaouchi NA, Va
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References 231 [126] Czuczman MS, G
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234 9 Tumour Vasculature Targeting
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256 10 Phage Display Technology for
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11 Development of Proteinaceous Dru
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carrier is an homogenous product. I
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11.3 The Homing Device 11.3 The Hom
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malian cell lines that have acquire
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jugates for the delivery of other a
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11.5 The Linkage Between Drug and C
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actions are directed towards these
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11.5 The Linkage Between Drug and C
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homing potential if the antigen rec
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ly used promoters include T7 RNA po
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the baculovirus expression vector,
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11.8 Recombinant DNA Constructs 297
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11.8 Recombinant DNA Constructs 299
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toxic activity. Anthrax and tetanus
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11.9 Recombinant Domains as Buildin
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References 305 [16] Milstein C, Wal
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References 307 [99] Verma R, Boleti
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12 Use of Human Tissue Slices in Dr
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are also extensively used in a vari
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Meanwhile many incubation systems h
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12.3 Incubation and Culture of Live
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to investigate the effect of differ
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The mechanisms of uptake and excret
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12.6 The Use of Liver Slices in Dru
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12.7 Efficacy Testing of the Drug T
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NO x µM 80 60 40 20 * * 12.7 Effic
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TNFα ng/ml 1.5 1 0.5 0 * Human (n=
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References 329 [33] Ikejima K, Enom
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References 331 [109] Dutt A, Priebe
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334 13 Pharmacokinetic/Pharmacodyna
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372 14 Drug Targeting Strategy: Scr
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374 14 Drug Targeting Strategy: Scr
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