{"product_id":"fusion-protein-technologies-for-biopharmaceuticals-isbn-9780470646274","title":"Fusion Protein Technologies for Biopharmaceuticals","description":"\u003cp\u003e\u003cb\u003eThe state of the art in biopharmaceutical FUSION PROTEIN DESIGN\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eFusion proteins belong to the most lucrative biotech drugs—with Enbrel® being one of the best-selling biologics worldwide. Enbrel® represents a milestone of modern therapies just as Humulin®, the first therapeutic recombinant protein for human use, approved by the FDA in 1982 and Orthoclone® the first monoclonal antibody reaching the market in 1986. These first generation molecules were soon followed by a plethora of recombinant copies of natural human proteins, and in 1998, the first de novo designed fusion protein was launched.\u003c\/p\u003e \u003cp\u003e\u003ci\u003eFusion Protein Technologies for Biopharmaceuticals\u003c\/i\u003e examines the state of the art in developing fusion proteins for biopharmaceuticals, shedding light on the immense potential inherent in fusion protein design and functionality. A wide pantheon of international scientists and researchers deliver a comprehensive and complete overview of therapeutic fusion proteins, combining the success stories of marketed drugs with the dynamic preclinical and clinical research into novel drugs designed for as yet unmet medical needs.\u003c\/p\u003e \u003cp\u003eThe book covers the major types of fusion proteins—receptor-traps, immunotoxins, Fc-fusions and peptibodies—while also detailing the approaches for developing, delivering, and improving the stability of fusion proteins. The main body of the book contains three large sections that address issues key to this specialty: strategies for extending the plasma half life, the design of toxic proteins, and utilizing fusion proteins for ultra specific targeting. The book concludes with novel concepts in this field, including examples of highly relevant multifunctional antibodies.\u003c\/p\u003e \u003cp\u003eDetailing the innovative science, commercial realities, and brilliant potential of fusion protein therapeutics, \u003ci\u003eFusion Protein Technologies for Biopharmaceuticals\u003c\/i\u003e is a must for pharmaceutical scientists, biochemists, medicinal chemists, molecular biologists, pharmacologists, and genetic engineers interested in determining the shape of innovation in the world of biopharmaceuticals.\u003c\/p\u003e  \u003cp\u003ePREFACE xxiii\u003c\/p\u003e \u003cp\u003eCONTRIBUTORS xxv\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePART I INTRODUCTION 1\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e1 Fusion Proteins: Applications and Challenges 3\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eStefan R. Schmidt\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e1.1 History, 3\u003c\/p\u003e \u003cp\u003e1.2 Definitions and Categories, 4\u003c\/p\u003e \u003cp\u003e1.3 Patenting, 5\u003c\/p\u003e \u003cp\u003e1.4 Design and Engineering, 6\u003c\/p\u003e \u003cp\u003e1.5 Manufacturing, 10\u003c\/p\u003e \u003cp\u003e1.6 Regulatory Challenges, 15\u003c\/p\u003e \u003cp\u003e1.7 Competition and Market, 16\u003c\/p\u003e \u003cp\u003e1.8 Conclusion and Future Perspective, 17\u003c\/p\u003e \u003cp\u003eReferences, 18\u003c\/p\u003e \u003cp\u003e\u003cb\u003e2 Analyzing and Forecasting the Fusion Protein Market and Pipeline 25\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eMark Belsey and Giles Somers\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e2.1 Introduction, 25\u003c\/p\u003e \u003cp\u003e2.2 Market Sales Dynamics of the FP Market, 25\u003c\/p\u003e \u003cp\u003e2.3 Individual Drug Sales Analysis, 27\u003c\/p\u003e \u003cp\u003e2.4 Pipeline Database Analysis, 32\u003c\/p\u003e \u003cp\u003eDisclaimer, 36\u003c\/p\u003e \u003cp\u003eAcknowledgment, 36\u003c\/p\u003e \u003cp\u003eReferences, 36\u003c\/p\u003e \u003cp\u003e\u003cb\u003e3 Structural Aspects of Fusion Proteins Determining the Level of Commercial Success 39\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eGiles Somers\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e3.1 Classification of FPs, 39\u003c\/p\u003e \u003cp\u003e3.2 Factors for Commercial Success, 49\u003c\/p\u003e \u003cp\u003eReferences, 54\u003c\/p\u003e \u003cp\u003e\u003cb\u003e4 Fusion Protein Linkers: Effects on Production, Bioactivity, and Pharmacokinetics 57\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eXiaoying Chen, Jennica Zaro, and Wei-Chiang Shen\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e4.1 Introduction, 57\u003c\/p\u003e \u003cp\u003e4.2 Overview of General Properties of Linkers Derived From Naturally Occurring Multidomain Proteins, 58\u003c\/p\u003e \u003cp\u003e4.3 Empirical Linkers in Recombinant Fusion Proteins, 59\u003c\/p\u003e \u003cp\u003e4.4 Functionality of Linkers in Fusion Proteins, 66\u003c\/p\u003e \u003cp\u003e4.5 Conclusions and Future Perspective, 70\u003c\/p\u003e \u003cp\u003eReferences, 71\u003c\/p\u003e \u003cp\u003e\u003cb\u003e5 Immunogenicity of Therapeutic Fusion Proteins: Contributory Factors and Clinical Experience 75\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eVibha Jawa, Leslie Cousens, and Anne S. De Groot\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e5.1 Introduction, 75\u003c\/p\u003e \u003cp\u003e5.2 Basis of Therapeutic Protein Immunogenicity, 75\u003c\/p\u003e \u003cp\u003e5.3 Tools for Immunogenicity Screening, 77\u003c\/p\u003e \u003cp\u003e5.4 Approaches for Risk Assessment and Minimization, 81\u003c\/p\u003e \u003cp\u003e5.5 Case Study and Clinical Experience, 83\u003c\/p\u003e \u003cp\u003e5.6 Preclinical and Clinical Immunogenicity Assessment Strategy, 85\u003c\/p\u003e \u003cp\u003e5.7 Conclusions, 87\u003c\/p\u003e \u003cp\u003eAcknowledgment, 87\u003c\/p\u003e \u003cp\u003eReferences, 87\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePART II THE TRIPLE T PARADIGM: TIME, TOXIN, TARGETING 91\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003eIIA TIME: FUSION PROTEIN STRATEGIES FOR HALF-LIFE EXTENSION 93\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e6 Fusion Proteins for Half-Life Extension 93\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eStefan R. Schmidt\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e6.1 Introduction, 93\u003c\/p\u003e \u003cp\u003e6.2 Half-Life Extension Through Size and Recycling, 94\u003c\/p\u003e \u003cp\u003e6.3 Half-Life Extension Through Increase of Hydrodynamic Radius, 100\u003c\/p\u003e \u003cp\u003e6.4 Aggregate Forming Peptide Fusions, 102\u003c\/p\u003e \u003cp\u003e6.5 Other Concepts, 103\u003c\/p\u003e \u003cp\u003e6.6 Conclusions and Future Perspective, 103\u003c\/p\u003e \u003cp\u003eReferences, 104\u003c\/p\u003e \u003cp\u003e\u003cb\u003e7 Monomeric Fc-Fusion Proteins 107\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eBaisong Mei, Susan C. Low, Snejana Krassova, Robert T. Peters, Glenn F. Pierce, and Jennifer A. Dumont\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e7.1 Introduction, 107\u003c\/p\u003e \u003cp\u003e7.2 FcRn and Monomeric Fc-Fusion Proteins, 108\u003c\/p\u003e \u003cp\u003e7.3 Typical Applications, 109\u003c\/p\u003e \u003cp\u003e7.4 Alternative Applications, 114\u003c\/p\u003e \u003cp\u003e7.5 Expression and Purification of Monomeric Fc-Fusion Proteins, 116\u003c\/p\u003e \u003cp\u003e7.6 Conclusions and Future Perspectives, 118\u003c\/p\u003e \u003cp\u003eReferences, 118\u003c\/p\u003e \u003cp\u003e\u003cb\u003e8 Peptide-Fc Fusion Therapeutics: Applications and Challenges 123\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eChichi Huang and Ronald V. Swanson\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e8.1 Introduction, 123\u003c\/p\u003e \u003cp\u003e8.2 Peptide Drugs, 124\u003c\/p\u003e \u003cp\u003e8.3 Technologies Used for Reducing In Vivo Clearance of Therapeutic Peptides, 126\u003c\/p\u003e \u003cp\u003e8.4 Fc-Fusion Proteins in Drug Development, 127\u003c\/p\u003e \u003cp\u003e8.5 Peptide-Fc-Fusion Therapeutics, 131\u003c\/p\u003e \u003cp\u003e8.6 Considerations and Challenges for Engineering Peptide-Fc-Fusion Therapeutics, 133\u003c\/p\u003e \u003cp\u003e8.7 Conclusions, 138\u003c\/p\u003e \u003cp\u003eAcknowledgment, 138\u003c\/p\u003e \u003cp\u003eReferences, 138\u003c\/p\u003e \u003cp\u003e\u003cb\u003e9 Receptor-Fc and Ligand Traps as High-Affinity Biological Blockers: Development and Clinical Applications 143\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eAris N. Economides and Neil Stahl\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e9.1 Introduction, 143\u003c\/p\u003e \u003cp\u003e9.2 Etanercept as a Prototypical Receptor-Fc-Based Cytokine Blocker, 144\u003c\/p\u003e \u003cp\u003e9.3 Heteromeric Traps for Ligands Utilizing Multicomponent Receptor Systems with Shared Subunits, 144\u003c\/p\u003e \u003cp\u003e9.4 Development and Clinical Application of an Interleukin 1 Trap: Rilonacept, 151\u003c\/p\u003e \u003cp\u003e9.5 Development and Clinical Application of a VEGF Trap, 151\u003c\/p\u003e \u003cp\u003e9.6 “To Trap Or Not To Trap?” Advantages and Disadvantages of Receptor-Fc Fusions and Traps Versus Antibodies, 152\u003c\/p\u003e \u003cp\u003e9.7 Conclusion, 155\u003c\/p\u003e \u003cp\u003eAcknowledgment, 155\u003c\/p\u003e \u003cp\u003eReferences, 155\u003c\/p\u003e \u003cp\u003e\u003cb\u003e10 Recombinant Albumin Fusion Proteins 163\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eThomas Weimer, Hubert J. Metzner, and Stefan Schulte\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e10.1 Concept, 163\u003c\/p\u003e \u003cp\u003e10.2 Technological Aspects, 164\u003c\/p\u003e \u003cp\u003e10.3 Typical Applications and Indications, 164\u003c\/p\u003e \u003cp\u003e10.4 Successes and Failures in Preclinical and Clinical Research, 172\u003c\/p\u003e \u003cp\u003e10.5 Challenges, 173\u003c\/p\u003e \u003cp\u003e10.6 Future Perspectives, 174\u003c\/p\u003e \u003cp\u003e10.7 Conclusion, 174\u003c\/p\u003e \u003cp\u003eAcknowledgment, 174\u003c\/p\u003e \u003cp\u003eReferences, 174\u003c\/p\u003e \u003cp\u003e\u003cb\u003e11 Albumin-Binding Fusion Proteins in the Development of Novel Long-Acting Therapeutics 179\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eAdam Walker, Grainne Dunlevy, and Peter Topley\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e11.1 Introduction, 179\u003c\/p\u003e \u003cp\u003e11.2 Clinically Validated Half-Life Extension Technologies—An Overview, 180\u003c\/p\u003e \u003cp\u003e11.3 Interferon-a Fused to Human Serum Albumin or AlbudAb—A Direct Comparison of HSA and AlbudAb Fusion Technologies, 182\u003c\/p\u003e \u003cp\u003e11.4 Nanobodies in the Development of Alternative Half-Life Extension Technologies Based on Single Immunoglobulin Variable Domains, 186\u003c\/p\u003e \u003cp\u003e11.5 Novel Half-Life Extension Technologies—Alternative Approaches to Single Immunoglobulin Variable Domains, 187\u003c\/p\u003e \u003cp\u003e11.6 Conclusions, 188\u003c\/p\u003e \u003cp\u003eReferences, 189\u003c\/p\u003e \u003cp\u003e\u003cb\u003e12 Transferrin Fusion Protein Therapies: Acetylcholine Receptor-Transferrin Fusion Protein as a Model 191\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eDennis Keefe, Michael Heartlein, and Serene Josiah\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e12.1 Disease Overview, 191\u003c\/p\u003e \u003cp\u003e12.2 Fusion Protein SHG2210 Design, 192\u003c\/p\u003e \u003cp\u003e12.3 Characterization of SHG2210, 193\u003c\/p\u003e \u003cp\u003e12.4 Applications and Indications, 196\u003c\/p\u003e \u003cp\u003e12.5 Future Perspectives, 197\u003c\/p\u003e \u003cp\u003e12.6 Conclusion, 198\u003c\/p\u003e \u003cp\u003eReferences, 198\u003c\/p\u003e \u003cp\u003e\u003cb\u003e13 Half-Life Extension Through O-Glycosylation 201\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eFuad Fares\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e13.1 Introduction, 201\u003c\/p\u003e \u003cp\u003e13.2 The Role of O-Linked Oligosaccharide Chains in Glycoprotein Function, 202\u003c\/p\u003e \u003cp\u003e13.3 Designing Long-Acting Agonists of Glycoprotein Hormones, 203\u003c\/p\u003e \u003cp\u003e13.4 Conclusions, 207\u003c\/p\u003e \u003cp\u003eReferences, 207\u003c\/p\u003e \u003cp\u003e\u003cb\u003e14 ELP-Fusion Technology for Biopharmaceuticals 211\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eDoreen M. Floss, Udo Conrad, Stefan Rose-John, and J€urgen Scheller\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e14.1 Introduction, 211\u003c\/p\u003e \u003cp\u003e14.2 ELP-based Protein Purification, 212\u003c\/p\u003e \u003cp\u003e14.3 ELPylated Proteins in Medicine and Nanobiotechnology, 215\u003c\/p\u003e \u003cp\u003e14.4 Molecular Pharming: a New Application for ELPylation, 217\u003c\/p\u003e \u003cp\u003e14.5 Challenges and Future Perspectives, 221\u003c\/p\u003e \u003cp\u003e14.6 Conclusion, 222\u003c\/p\u003e \u003cp\u003eReferences, 222\u003c\/p\u003e \u003cp\u003e\u003cb\u003e15 Ligand-Receptor Fusion Dimers 227\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eSarbendra L. Pradhananga, Ian R. Wilkinson, Eric Ferrandis, Peter J. Artymiuk, Jon R. Sayers, and Richard J. Ross\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e15.1 Introduction, 227\u003c\/p\u003e \u003cp\u003e15.2 The GHLR-Fusions, 228\u003c\/p\u003e \u003cp\u003e15.3 Expression and Purification, 229\u003c\/p\u003e \u003cp\u003e15.4 Analysis of the LR-Fusions, 229\u003c\/p\u003e \u003cp\u003e15.5 LR-Fusions: The Next Generation in Hormone Treatment, 234\u003c\/p\u003e \u003cp\u003e15.6 Conclusion, 234\u003c\/p\u003e \u003cp\u003eReferences, 234\u003c\/p\u003e \u003cp\u003e\u003cb\u003e16 Development of Latent Cytokine Fusion Proteins 237\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eLisa Mullen, Gill Adams, Rewas Fatah, David Gould, Anne Rigby, Michelle Sclanders, Apostolos Koutsokeras, Gayatri Mittal, Sandrine Vessillier, and Yuti Chernajovsky\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e16.1 Introduction, 237\u003c\/p\u003e \u003cp\u003e16.2 Description of Concept, 238\u003c\/p\u003e \u003cp\u003e16.3 Limitations of the Latent Cytokine Technology, 240\u003c\/p\u003e \u003cp\u003e16.4 Generation of Latent Cytokines, 242\u003c\/p\u003e \u003cp\u003e16.5 Applications and Potential Clinical Indications, 244\u003c\/p\u003e \u003cp\u003e16.6 Alternatives\/Variants of Approach, 246\u003c\/p\u003e \u003cp\u003e16.7 Challenges (Production and Development), 247\u003c\/p\u003e \u003cp\u003e16.8 Conclusions and Future Perspectives, 248\u003c\/p\u003e \u003cp\u003eAcknowledgments, 249\u003c\/p\u003e \u003cp\u003eReferences, 249\u003c\/p\u003e \u003cp\u003e\u003cb\u003eIIB TOXIN: CYTOTOXIC FUSION PROTEINS 253\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e17 Fusion Proteins with Toxic Activity 253\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eStefan R. Schmidt\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e17.1 Introduction, 253\u003c\/p\u003e \u003cp\u003e17.2 Toxins, 254\u003c\/p\u003e \u003cp\u003e17.3 Immunocytokines, 258\u003c\/p\u003e \u003cp\u003e17.4 Human Enzymes, 259\u003c\/p\u003e \u003cp\u003e17.5 Apoptosis Induction, 261\u003c\/p\u003e \u003cp\u003e17.6 Fc-Based Toxicity, 263\u003c\/p\u003e \u003cp\u003e17.7 Peptide-Based Toxicity, 264\u003c\/p\u003e \u003cp\u003e17.8 Conclusions and Future Perspectives, 265\u003c\/p\u003e \u003cp\u003eReferences, 265\u003c\/p\u003e \u003cp\u003e\u003cb\u003e18 Classic Immunotoxins with Plant or Microbial Toxins 271\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eJung Hee Woo and Arthur Frankel\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e18.1 Introduction, 271\u003c\/p\u003e \u003cp\u003e18.2 Toxins Used in Immunotoxin Preparation, 272\u003c\/p\u003e \u003cp\u003e18.3 Immunotoxin Design and Synthesis, 274\u003c\/p\u003e \u003cp\u003e18.4 Clinical Update of Immunotoxin Trials, 278\u003c\/p\u003e \u003cp\u003e18.5 Challenges and Perspective of Classic Immunotoxins, 284\u003c\/p\u003e \u003cp\u003e18.6 Conclusions, 286\u003c\/p\u003e \u003cp\u003eReferences, 286\u003c\/p\u003e \u003cp\u003e\u003cb\u003e19 Targeted and Untargeted Fusion Proteins: Current Approaches to Cancer Immunotherapy 295\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eLeslie A. Khawli, Peisheng Hu, and Alan L. Epstein\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e19.1 Introduction, 295\u003c\/p\u003e \u003cp\u003e19.2 Immunotherapeutic Strategy for Cancer: Fusion Proteins, 296\u003c\/p\u003e \u003cp\u003e19.3 Immunotherapeutic Applications of Antibody-Targeted and Untargeted Fc Fusion Proteins, 297\u003c\/p\u003e \u003cp\u003e19.4 Combination Fusion Proteins Therapy, 305\u003c\/p\u003e \u003cp\u003e19.5 Mechanism of Action: Immunoregulatory T-Cell (Treg) Depletion and Fusion Protein Combination Therapy, 306\u003c\/p\u003e \u003cp\u003e19.6 Future Directions, 309\u003c\/p\u003e \u003cp\u003e19.7 Conclusion, 309\u003c\/p\u003e \u003cp\u003eAcknowledgments, 310\u003c\/p\u003e \u003cp\u003eReferences, 310\u003c\/p\u003e \u003cp\u003e\u003cb\u003e20 Development of Experimental Targeted Toxin Therapies for Malignant Glioma 315\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eNikolai G. Rainov and Volkmar Heidecke\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e20.1 Introduction, 315\u003c\/p\u003e \u003cp\u003e20.2 Targeted Toxins—General Considerations, 316\u003c\/p\u003e \u003cp\u003e20.3 Delivery Mode and Pharmacokinetics of Targeted Toxins in the Brain, 316\u003c\/p\u003e \u003cp\u003e20.4 Preclinical and Clinical Studies with Targeted Toxins, 318\u003c\/p\u003e \u003cp\u003e20.5 Conclusions and Future Developments of Targeted Toxins, 324\u003c\/p\u003e \u003cp\u003eDisclosure, 325\u003c\/p\u003e \u003cp\u003eReferences, 325\u003c\/p\u003e \u003cp\u003e\u003cb\u003e21 Immunokinases 329\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eStefan Barth, Stefan Gattenl€ohner, and Mehmet Kemal Tur\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e21.1 Introduction, 329\u003c\/p\u003e \u003cp\u003e21.2 Protein Kinases, Apoptosis, and Cancer, 330\u003c\/p\u003e \u003cp\u003e21.3 Therapeutic Strategies to Restore Missing Kinase Expression, 331\u003c\/p\u003e \u003cp\u003e21.4 Analysis of Immunokinase Efficacy, 333\u003c\/p\u003e \u003cp\u003e21.5 Outlook, 334\u003c\/p\u003e \u003cp\u003eReferences, 334\u003c\/p\u003e \u003cp\u003e\u003cb\u003e22 ImmunoRNase Fusions 337\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eWojciech Ardelt\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e22.1 Introduction, 337\u003c\/p\u003e \u003cp\u003e22.2 Development of ImmunoRNase Fusion Proteins as Biopharmaceuticals, 339\u003c\/p\u003e \u003cp\u003e22.3 Aspects of ImmunoRNase Design and Production, 344\u003c\/p\u003e \u003cp\u003e22.4 Alternatives, 346\u003c\/p\u003e \u003cp\u003e22.5 Conclusions and Future Perspectives, 347\u003c\/p\u003e \u003cp\u003eReferences, 347\u003c\/p\u003e \u003cp\u003e\u003cb\u003e23 Antibody-Directed Enzyme Prodrug Therapy (ADEPT) 355\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eSurinder K. Sharma\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e23.1 Introduction, 355\u003c\/p\u003e \u003cp\u003e23.2 The Components, 355\u003c\/p\u003e \u003cp\u003e23.3 ADEPT Systems with Carboxypeptidase G2 (CPG2), 357\u003c\/p\u003e \u003cp\u003e23.4 Fusion Proteins, 359\u003c\/p\u003e \u003cp\u003e23.5 Immunogenicity, 360\u003c\/p\u003e \u003cp\u003e23.6 Conclusions and Future Outlook, 361\u003c\/p\u003e \u003cp\u003eAcknowledgments, 361\u003c\/p\u003e \u003cp\u003eReferences, 361\u003c\/p\u003e \u003cp\u003e\u003cb\u003e24 Tumor-Targeted Superantigens 365\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eGunnar Hedlund, G€oran Forsberg, Thore Nederman, Anette Sundstedt, Leif Dahlberg, Mikael Tiensuu, and Mats Nilsson\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e24.1 Introduction: Tumor-Targeted Superantigens—AUnique Concept of Cancer Treatment, 365\u003c\/p\u003e \u003cp\u003e24.2 Structure and Production of Tumor-Targeted Superantigens, 366\u003c\/p\u003e \u003cp\u003e24.3 Tumor-Targeted Superantigens are Powerful Targeted Immune Activators and Useful for all Types of Malignancies, 367\u003c\/p\u003e \u003cp\u003e24.4 Increasing the Therapeutic Window and Exposure by the Creation of a Novel TTS Fusion Protein with Minimal MHC Class II Affinity; Naptumomab Estafenatox, 370\u003c\/p\u003e \u003cp\u003e24.5 Clinical Experience with TTS Therapeutic Fusion Proteins, 371\u003c\/p\u003e \u003cp\u003e24.6 Combining TTS with Cytostatic and Immunomodulating Anticancer Drugs, 377\u003c\/p\u003e \u003cp\u003e24.7 Conclusions, 379\u003c\/p\u003e \u003cp\u003eReferences, 379\u003c\/p\u003e \u003cp\u003e\u003cb\u003eIIC TARGETING: FUSION PROTEINS ADDRESSING SPECIFIC CELLS, ORGANS, AND TISSUES 383\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e25 Fusion Proteins with a Targeting Function 383\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eStefan R. Schmidt\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e25.1 Introduction, 383\u003c\/p\u003e \u003cp\u003e25.2 Targeting Organs, 383\u003c\/p\u003e \u003cp\u003e25.3 Intracellular Delivery, 388\u003c\/p\u003e \u003cp\u003e25.4 Oral Delivery, 391\u003c\/p\u003e \u003cp\u003e25.5 Conclusions and Future Perspectives, 392\u003c\/p\u003e \u003cp\u003eReferences, 393\u003c\/p\u003e \u003cp\u003e\u003cb\u003e26 Cell-Penetrating Peptide Fusion Proteins 397\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eAndres Mu~noz-Alarcon, Henrik Helmfors, Kristin Karlsson, and €U lo Langel\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e26.1 Introduction, 397\u003c\/p\u003e \u003cp\u003e26.2 Typical Applications and Indications, 397\u003c\/p\u003e \u003cp\u003e26.3 Technological Aspects, 399\u003c\/p\u003e \u003cp\u003e26.4 Successes and Failures in Preclinical and Clinical Research, 402\u003c\/p\u003e \u003cp\u003e26.5 Alternatives\/Variants of This Approach, 405\u003c\/p\u003e \u003cp\u003e26.6 Conclusions and Future Perspectives, 405\u003c\/p\u003e \u003cp\u003eAcknowledgments, 406\u003c\/p\u003e \u003cp\u003eReferences, 406\u003c\/p\u003e \u003cp\u003e\u003cb\u003e27 Cell-Specific Targeting of Fusion Proteins through Heparin Binding 413\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eJiajing Wang, Zhenzhong Ma, and Jeffrey A. Loeb\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e27.1 Why Target Heparan-Sulfate Proteoglycans with Fusion Proteins?, 413\u003c\/p\u003e \u003cp\u003e27.2 Heparan Sulfate Structure and Biosynthesis Create Diversity and a Template for Targeting Specificity, 415\u003c\/p\u003e \u003cp\u003e27.3 Tissue-Specific Expression of HSPGs and the Enzymes That Modify Them, 416\u003c\/p\u003e \u003cp\u003e27.4 Heparin-Binding Proteins and Growth Factors, 416\u003c\/p\u003e \u003cp\u003e27.5 Viruses Target Cells Through Heparin Binding, 417\u003c\/p\u003e \u003cp\u003e27.6 Dissecting Heparin-Binding Protein Domains for Tissue-Specific Targeting, 418\u003c\/p\u003e \u003cp\u003e27.7 Fusion Proteins Incorporating HBDs, 418\u003c\/p\u003e \u003cp\u003e27.8 The Neuregulin 1 Growth Factor Has a Unique and Highly Specific HBD, 419\u003c\/p\u003e \u003cp\u003e27.9 Using Neuregulin’s HBD to Generate a Targeted Neuregulin Antagonist, 419\u003c\/p\u003e \u003cp\u003e27.10 Tissue Targeting and Therapeutic Efficacy of a Heparin-Targeted NRG1 Antagonist Fusion Protein, 420\u003c\/p\u003e \u003cp\u003e27.11 Conclusions and Future Perspectives, 423\u003c\/p\u003e \u003cp\u003eReferences, 424\u003c\/p\u003e \u003cp\u003e\u003cb\u003e28 Bone-Targeted Alkaline Phosphatase 429\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eJose Luis Millan\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e28.1 Detailed Description of the Concept, 429\u003c\/p\u003e \u003cp\u003e28.2 Technical Aspects, 430\u003c\/p\u003e \u003cp\u003e28.3 Applications and Indications, 432\u003c\/p\u003e \u003cp\u003e28.4 Preclinical and Clinical Research, 433\u003c\/p\u003e \u003cp\u003e28.5 Alternatives\/Variants of This Approach, 434\u003c\/p\u003e \u003cp\u003e28.6 Challenges in Production and Development, 436\u003c\/p\u003e \u003cp\u003e28.7 Conclusions and Future Perspectives, 436\u003c\/p\u003e \u003cp\u003eAcknowledgments, 437\u003c\/p\u003e \u003cp\u003eReferences, 437\u003c\/p\u003e \u003cp\u003e\u003cb\u003e29 Targeting Interferon-a to the Liver: Apolipoprotein A-I as a Scaffold for Protein Delivery 441\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eJessica Fioravanti, Jesus Prieto, and Pedro Berraondo\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e29.1 Detailed Description of the Concept, 441\u003c\/p\u003e \u003cp\u003e29.2 Technological Aspects, 447\u003c\/p\u003e \u003cp\u003e29.3 Typical Applications and Indications, 447\u003c\/p\u003e \u003cp\u003e29.4 Alternatives and Variants of This Approach, 448\u003c\/p\u003e \u003cp\u003e29.5 Conclusions and Future Perspectives, 448\u003c\/p\u003e \u003cp\u003eReferences, 448\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePART III BEYOND THE TRIPLE T-PARADIGM 453\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003eIIIA NOVEL CONCEPTS, NOVEL SCAFFOLDS 455\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e30 Signal Converter Proteins 455\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eMark L. Tykocinski\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e30.1 Introduction, 455\u003c\/p\u003e \u003cp\u003e30.2 Historical Roots of Signal Conversion: Artificial Veto Cell Engineering and Protein Painting, 455\u003c\/p\u003e \u003cp\u003e30.3 Trans Signal Converter Proteins, 458\u003c\/p\u003e \u003cp\u003e30.4 Expanding Trans Signal Conversion Options: Redirecting Signals, 459\u003c\/p\u003e \u003cp\u003e30.5 From Trans to Cis Signal Conversion: Driving Auto-Signaling, 460\u003c\/p\u003e \u003cp\u003e30.6 Mechanistic Dividends of Chimerization, 461\u003c\/p\u003e \u003cp\u003e30.7 Targeting Multiple Diseases with Individual Signal Converters, 462\u003c\/p\u003e \u003cp\u003e30.8 Structural Constraints in SCP Design, 463\u003c\/p\u003e \u003cp\u003e30.9 Coding SCP Functional Repertoires, 463\u003c\/p\u003e \u003cp\u003e30.10 Expanding the Catalog of Inhibitory SCP, 464\u003c\/p\u003e \u003cp\u003e30.11 Immune Activating SCP, 466\u003c\/p\u003e \u003cp\u003e30.12 Experimental Tools for Screening SCP Candidates, 467\u003c\/p\u003e \u003cp\u003e30.13 SCP Frontiers: Mining the Surface Protein Interactome, Rewiring Cellular Networks, 467\u003c\/p\u003e \u003cp\u003eReferences, 468\u003c\/p\u003e \u003cp\u003e\u003cb\u003e31 Soluble T-Cell Antigen Receptors 475\u003c\/b\u003e\u003cbr\u003e \u003ci\u003ePeter R. Rhode\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e31.1 Soluble T-cell Antigen Receptor (STAR) Fusion Technology and Utilities, 475\u003c\/p\u003e \u003cp\u003e31.2 Expression and Purification of Recombinant Star Fusion Proteins, 477\u003c\/p\u003e \u003cp\u003e31.3 Clinical and Research Product Applications, 478\u003c\/p\u003e \u003cp\u003e31.4 Preclinical Testing Using Star Fusion Proteins, 481\u003c\/p\u003e \u003cp\u003e31.5 Clinical Development of ALT-801, 487\u003c\/p\u003e \u003cp\u003e31.6 Alternatives\/Variants of This Approach, 488\u003c\/p\u003e \u003cp\u003e31.7 Challenges, 489\u003c\/p\u003e \u003cp\u003e31.8 Conclusions and Future Perspectives, 490\u003c\/p\u003e \u003cp\u003eAcknowledgments, 490\u003c\/p\u003e \u003cp\u003eReferences, 490\u003c\/p\u003e \u003cp\u003e\u003cb\u003e32 High-Affinity Monoclonal T-Cell Receptor (mTCR) Fusions 495\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eNikolai M. Lissin, Namir J. Hassan, and Bent K. Jakobsen\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e32.1 Introduction: The T Cell Receptor (TCR) as a Targeting Molecule, 495\u003c\/p\u003e \u003cp\u003e32.2 Engineered High-Affinity Monoclonal TCRs (mTCR), 497\u003c\/p\u003e \u003cp\u003e32.3 mTCR-Based Fusion Proteins for Therapeutic Applications, 500\u003c\/p\u003e \u003cp\u003e32.4 Immune-Mobilizing Monoclonal TCRs Against Cancer (ImmTAC), 500\u003c\/p\u003e \u003cp\u003e32.5 Conclusions and Future Perspectives, 503\u003c\/p\u003e \u003cp\u003eAcknowledgments, 504\u003c\/p\u003e \u003cp\u003eReferences, 504\u003c\/p\u003e \u003cp\u003e\u003cb\u003e33 Amediplase 507\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eStefano Evangelista and Stefano Manzini\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e33.1 Introduction, 507\u003c\/p\u003e \u003cp\u003e33.2 Source, Physico-Chemical Properties and Formulation, 508\u003c\/p\u003e \u003cp\u003e33.3 Preclinical Studies, 510\u003c\/p\u003e \u003cp\u003e33.4 Human Studies, 512\u003c\/p\u003e \u003cp\u003e33.5 Historical Comparison with Other Thrombolytics, 517\u003c\/p\u003e \u003cp\u003e33.6 Conclusions and Future Perspectives, 517\u003c\/p\u003e \u003cp\u003eAcknowledgment, 517\u003c\/p\u003e \u003cp\u003eReferences, 517\u003c\/p\u003e \u003cp\u003e\u003cb\u003e34 Breaking New Therapeutic Grounds: Fusion Proteins of Darpins and Other Nonantibody Binding Proteins 519\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eHans Kaspar Binz\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e34.1 Introduction, 519\u003c\/p\u003e \u003cp\u003e34.2 Novel Scaffolds—Alternatives to Antibodies, 519\u003c\/p\u003e \u003cp\u003e34.3 New Therapeutic Concepts with Nonantibody Binding Proteins, 523\u003c\/p\u003e \u003cp\u003e34.4 Scaffold-Fusion Proteins Beyond Antibody Possibilities, 525\u003c\/p\u003e \u003cp\u003eAcknowledgments, 526\u003c\/p\u003e \u003cp\u003eReferences, 526\u003c\/p\u003e \u003cp\u003e\u003cb\u003eIIIB MULTIFUNCTIONAL ANTIBODIES 529\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e35 Resurgence of Bispecific Antibodies 529\u003c\/b\u003e\u003cbr\u003e \u003ci\u003ePatrick A. Baeuerle and Tobias Raum\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e35.1 A Brief History of Bispecific Antibodies, 529\u003c\/p\u003e \u003cp\u003e35.2 Asymmetric IgG-Like Bispecific Antibodies, 530\u003c\/p\u003e \u003cp\u003e35.3 Symmetric IgG-Like Bispecific Antibodies, 531\u003c\/p\u003e \u003cp\u003e35.4 IgG-Like Bispecific Antibodies with Fused Antibody Fragments, 533\u003c\/p\u003e \u003cp\u003e35.5 Bispecific Constructs Based on the Fcg Fragment, 534\u003c\/p\u003e \u003cp\u003e35.6 Bispecific Constructs Based on Fab Fragments, 535\u003c\/p\u003e \u003cp\u003e35.7 Bispecific Constructs Based on Diabodies or Single-Chain Antibodies, 536\u003c\/p\u003e \u003cp\u003e35.8 Bifunctional Fusions of Antibodies or Fragments with Other Proteins, 538\u003c\/p\u003e \u003cp\u003e35.9 Bispecific Antibodies for Various Functions: How to Select the Right Format?, 539\u003c\/p\u003e \u003cp\u003eReferences, 541\u003c\/p\u003e \u003cp\u003e\u003cb\u003e36 Novel Applications of Bispecific DART1 Proteins 545\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eSyd Johnson, Bhaswati Barat, Hua W. Li, Ralph F. Alderson, Paul A. Moore, and\u003c\/i\u003e Ezio \u003ci\u003eBonvini\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e36.1 Introduction, 545\u003c\/p\u003e \u003cp\u003e36.2 DART1 Proteins, 546\u003c\/p\u003e \u003cp\u003e36.3 Application of DART1 to Cross-Link Inhibitory and Activating Receptors, 546\u003c\/p\u003e \u003cp\u003e36.4 Application of Bispecific Antibodies in Oncology, 547\u003c\/p\u003e \u003cp\u003e36.5 U-DART Concept for Screening DART1 Candidate Targets and mAbs, 549\u003c\/p\u003e \u003cp\u003e36.6 U-DART Concept for Applications in Autoimmune and Inflammatory Disease, 549\u003c\/p\u003e \u003cp\u003e36.7 Conclusions and Future Perspectives, 554\u003c\/p\u003e \u003cp\u003eReferences, 554\u003c\/p\u003e \u003cp\u003e\u003cb\u003e37 Strand Exchange Engineered Domain\u003c\/b\u003e \u003cb\u003e(Seed): A Novel Platform Designed to Generate Mono and Multispecific Protein Therapeutics 557\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eAlec W. Gross, Jessica P. Dawson, Marco Muda, Christie Kelton, Sean D. McKenna, and Bjo¨rn Hock\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e37.1 Introduction, 557\u003c\/p\u003e \u003cp\u003e37.2 Technical Aspects, 558\u003c\/p\u003e \u003cp\u003e37.3 Potential Therapeutic Applications, 562\u003c\/p\u003e \u003cp\u003e37.4 Future Perspectives, 566\u003c\/p\u003e \u003cp\u003e37.5 Conclusions, 567\u003c\/p\u003e \u003cp\u003eAcknowledgments, 567\u003c\/p\u003e \u003cp\u003eReferences, 567\u003c\/p\u003e \u003cp\u003e\u003cb\u003e38 CovX-Bodies 571\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eAbhijit Bhat, Olivier Laurent, and Rodney Lappe\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e38.1 The CovX-Body Concept, 571\u003c\/p\u003e \u003cp\u003e38.2 Technological Aspects, 571\u003c\/p\u003e \u003cp\u003e38.3 Applications of the CovX-Body Technology, 578\u003c\/p\u003e \u003cp\u003eReferences, 581\u003c\/p\u003e \u003cp\u003e\u003cb\u003e39 Modular Antibody Engineering: Antigen Binding Immunoglobulin Fc CH3 Domains as Building Blocks for Bispecific Antibodies (mAb2) 583\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eMaximilian Woisetschl€ager, Florian R€uker, Geert C. Mudde, Gordana Wozniak-Knopp, Anton Bauer, and Gottfried Himmler\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e39.1 Introduction, 583\u003c\/p\u003e \u003cp\u003e39.2 Immunoglobulin Fc as a Scaffold, 583\u003c\/p\u003e \u003cp\u003e39.3 Design of Libraries Based on the Human IgG1 CH3 Domain, 584\u003c\/p\u003e \u003cp\u003e39.4 TNF-a-Binding Fcab: Selection and Characterization of Fcab TNF353-2, 585\u003c\/p\u003e \u003cp\u003e39.5 Conclusions and Future Perspectives, 588\u003c\/p\u003e \u003cp\u003eAcknowledgments, 588\u003c\/p\u003e \u003cp\u003eReferences, 589\u003c\/p\u003e \u003cp\u003e\u003cb\u003e40 Designer Fusion Modules for Building Multifunctional, Multivalent Antibodies, and Immunoconjugates: The Dock-and-Lock Method 591\u003c\/b\u003e\u003cbr\u003e \u003ci\u003eEdmund A. Rossi, David M. Goldenberg, and Chien-Hsing Chang\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e40.1 Introduction, 591\u003c\/p\u003e \u003cp\u003e40.2 DDD\/AD Modules Based on PKA and AKAP, 592\u003c\/p\u003e \u003cp\u003e40.3 Advantages and Disadvantages of the DNL Method, 592\u003c\/p\u003e \u003cp\u003e40.4 Fab-Based Modules, 593\u003c\/p\u003e \u003cp\u003e40.5 IgG-AD2-Modules, 594\u003c\/p\u003e \u003cp\u003e40.6 Hexavalent Antibodies, 595\u003c\/p\u003e \u003cp\u003e40.7 More Antibody-Based-Modules and Multivalent Antibodies, 596\u003c\/p\u003e \u003cp\u003e40.8 Nonantibody-Based DNL Modules, 597\u003c\/p\u003e \u003cp\u003e40.9 IFN-a2b-DDD2 Module and Immunocytokines, 597\u003c\/p\u003e \u003cp\u003e40.10 Variations on the DNLTheme, 598\u003c\/p\u003e \u003cp\u003e40.11 Conclusions and Future Perspective, 599\u003c\/p\u003e \u003cp\u003eReferences, 599\u003c\/p\u003e \u003cp\u003eINDEX 603\u003c\/p\u003e \u003cp\u003e“Overall, this book is a “bona fide” companion for newcomers, as well as for experts in the pharmaceutical industry, in biotechnology or universities with affiliations to industry and medicine.”  (\u003ci\u003emAbs\u003c\/i\u003e, 15 April 2015)\u003c\/p\u003e \u003cp\u003e\u003cb\u003eSTEFAN R. SCHMIDT, PhD\u003c\/b\u003e, is Vice President for Downstream Processing at Rentschler Biotechnology. Previously, he served as CSO at ERA Biotech and Associate Director for Protein Science at AstraZeneca. Dr. Schmidt has chaired many international conferences and written several original articles, reviews, and book chapters.\u003c\/p\u003e   \u003cp\u003e\u003cb\u003eThe state of the art in biopharmaceutical FUSION PROTEIN DESIGN\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003eFusion proteins belong to the most lucrative biotech drugs—with Enbrel® being one of the best-selling biologics worldwide. Enbrel® represents a milestone of modern therapies just as Humulin®, the first therapeutic recombinant protein for human use, approved by the FDA in 1982 and Orthoclone® the first monoclonal antibody reaching the market in 1986. These first generation molecules were soon followed by a plethora of recombinant copies of natural human proteins, and in 1998, the first de novo designed fusion protein was launched.\u003c\/p\u003e \u003cp\u003e\u003ci\u003eFusion Protein Technologies for Biopharmaceuticals\u003c\/i\u003e examines the state of the art in developing fusion proteins for biopharmaceuticals, shedding light on the immense potential inherent in fusion protein design and functionality. A wide pantheon of international scientists and researchers deliver a comprehensive and complete overview of therapeutic fusion proteins, combining the success stories of marketed drugs with the dynamic preclinical and clinical research into novel drugs designed for as yet unmet medical needs.\u003c\/p\u003e \u003cp\u003eThe book covers the major types of fusion proteins—receptor-traps, immunotoxins, Fc-fusions and peptibodies—while also detailing the approaches for developing, delivering, and improving the stability of fusion proteins. The main body of the book contains three large sections that address issues key to this specialty: strategies for extending the plasma half life, the design of toxic proteins, and utilizing fusion proteins for ultra specific targeting. The book concludes with novel concepts in this field, including examples of highly relevant multifunctional antibodies.\u003c\/p\u003e \u003cp\u003eDetailing the innovative science, commercial realities, and brilliant potential of fusion protein therapeutics, \u003ci\u003eFusion Protein Technologies for Biopharmaceuticals\u003c\/i\u003e is a must for pharmaceutical scientists, biochemists, medicinal chemists, molecular biologists, pharmacologists, and genetic engineers interested in determining the shape of innovation in the world of biopharmaceuticals.\u003c\/p\u003e","brand":"Wiley","offers":[{"title":"Default Title","offer_id":47989267005669,"sku":"NP9780470646274","price":231.95,"currency_code":"USD","in_stock":false}],"thumbnail_url":"\/\/cdn.shopify.com\/s\/files\/1\/1842\/7735\/files\/9780470646274.jpg?v=1761783446","url":"https:\/\/k12savings.com\/es\/products\/fusion-protein-technologies-for-biopharmaceuticals-isbn-9780470646274","provider":"K12savings","version":"1.0","type":"link"}