Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges

Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges

By: Stefan R. Schmidt (editor)Hardback

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Description

This book presents the state-of-the-art for development of fusion proteins, demonstrates current concepts, describes multiple applications, and discusses typical challenges linked to these molecules. It overviews the multitude of possibilities to design novel protein drugs while balancing between proven concepts and new ideas that have not reached the clinic yet. The book is structured into three larger parts. First general issues and concepts are discussed before in the second part examples on the three categories (time, toxicity, and targeting) are presented. Finally, novel concepts and the rising class of multispecifc antibodies are described. Together, the chapters combine the success stories of marketed drugs with the dynamic preclinical and clinical research into novel drugs addressing unmet medical needs.

About Author

STEFAN R. SCHMIDT, PhD, 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.

Contents

PREFACE xxiii CONTRIBUTORS xxv PART I INTRODUCTION 1 1 Fusion Proteins: Applications and Challenges 3 Stefan R. Schmidt 1.1 History, 3 1.2 Definitions and Categories, 4 1.3 Patenting, 5 1.4 Design and Engineering, 6 1.5 Manufacturing, 10 1.6 Regulatory Challenges, 15 1.7 Competition and Market, 16 1.8 Conclusion and Future Perspective, 17 References, 18 2 Analyzing and Forecasting the Fusion Protein Market and Pipeline 25 Mark Belsey and Giles Somers 2.1 Introduction, 25 2.2 Market Sales Dynamics of the FP Market, 25 2.3 Individual Drug Sales Analysis, 27 2.4 Pipeline Database Analysis, 32 Disclaimer, 36 Acknowledgment, 36 References, 36 3 Structural Aspects of Fusion Proteins Determining the Level of Commercial Success 39 Giles Somers 3.1 Classification of FPs, 39 3.2 Factors for Commercial Success, 49 References, 54 4 Fusion Protein Linkers: Effects on Production, Bioactivity, and Pharmacokinetics 57 Xiaoying Chen, Jennica Zaro, and Wei-Chiang Shen 4.1 Introduction, 57 4.2 Overview of General Properties of Linkers Derived From Naturally Occurring Multidomain Proteins, 58 4.3 Empirical Linkers in Recombinant Fusion Proteins, 59 4.4 Functionality of Linkers in Fusion Proteins, 66 4.5 Conclusions and Future Perspective, 70 References, 71 5 Immunogenicity of Therapeutic Fusion Proteins: Contributory Factors and Clinical Experience 75 Vibha Jawa, Leslie Cousens, and Anne S. De Groot 5.1 Introduction, 75 5.2 Basis of Therapeutic Protein Immunogenicity, 75 5.3 Tools for Immunogenicity Screening, 77 5.4 Approaches for Risk Assessment and Minimization, 81 5.5 Case Study and Clinical Experience, 83 5.6 Preclinical and Clinical Immunogenicity Assessment Strategy, 85 5.7 Conclusions, 87 Acknowledgment, 87 References, 87 PART II THE TRIPLE T PARADIGM: TIME, TOXIN, TARGETING 91 IIA TIME: FUSION PROTEIN STRATEGIES FOR HALF-LIFE EXTENSION 93 6 Fusion Proteins for Half-Life Extension 93 Stefan R. Schmidt 6.1 Introduction, 93 6.2 Half-Life Extension Through Size and Recycling, 94 6.3 Half-Life Extension Through Increase of Hydrodynamic Radius, 100 6.4 Aggregate Forming Peptide Fusions, 102 6.5 Other Concepts, 103 6.6 Conclusions and Future Perspective, 103 References, 104 7 Monomeric Fc-Fusion Proteins 107 Baisong Mei, Susan C. Low, Snejana Krassova, Robert T. Peters, Glenn F. Pierce, and Jennifer A. Dumont 7.1 Introduction, 107 7.2 FcRn and Monomeric Fc-Fusion Proteins, 108 7.3 Typical Applications, 109 7.4 Alternative Applications, 114 7.5 Expression and Purification of Monomeric Fc-Fusion Proteins, 116 7.6 Conclusions and Future Perspectives, 118 References, 118 8 Peptide-Fc Fusion Therapeutics: Applications and Challenges 123 Chichi Huang and Ronald V. Swanson 8.1 Introduction, 123 8.2 Peptide Drugs, 124 8.3 Technologies Used for Reducing In Vivo Clearance of Therapeutic Peptides, 126 8.4 Fc-Fusion Proteins in Drug Development, 127 8.5 Peptide-Fc-Fusion Therapeutics, 131 8.6 Considerations and Challenges for Engineering Peptide-Fc-Fusion Therapeutics, 133 8.7 Conclusions, 138 Acknowledgment, 138 References, 138 9 Receptor-Fc and Ligand Traps as High-Affinity Biological Blockers: Development and Clinical Applications 143 Aris N. Economides and Neil Stahl 9.1 Introduction, 143 9.2 Etanercept as a Prototypical Receptor-Fc-Based Cytokine Blocker, 144 9.3 Heteromeric Traps for Ligands Utilizing Multicomponent Receptor Systems with Shared Subunits, 144 9.4 Development and Clinical Application of an Interleukin 1 Trap: Rilonacept, 151 9.5 Development and Clinical Application of a VEGF Trap, 151 9.6 To Trap Or Not To Trap? Advantages and Disadvantages of Receptor-Fc Fusions and Traps Versus Antibodies, 152 9.7 Conclusion, 155 Acknowledgment, 155 References, 155 10 Recombinant Albumin Fusion Proteins 163 Thomas Weimer, Hubert J. Metzner, and Stefan Schulte 10.1 Concept, 163 10.2 Technological Aspects, 164 10.3 Typical Applications and Indications, 164 10.4 Successes and Failures in Preclinical and Clinical Research, 172 10.5 Challenges, 173 10.6 Future Perspectives, 174 10.7 Conclusion, 174 Acknowledgment, 174 References, 174 11 Albumin-Binding Fusion Proteins in the Development of Novel Long-Acting Therapeutics 179 Adam Walker, Grainne Dunlevy, and Peter Topley 11.1 Introduction, 179 11.2 Clinically Validated Half-Life Extension Technologies An Overview, 180 11.3 Interferon-a Fused to Human Serum Albumin or AlbudAb A Direct Comparison of HSA and AlbudAb Fusion Technologies, 182 11.4 Nanobodies in the Development of Alternative Half-Life Extension Technologies Based on Single Immunoglobulin Variable Domains, 186 11.5 Novel Half-Life Extension Technologies Alternative Approaches to Single Immunoglobulin Variable Domains, 187 11.6 Conclusions, 188 References, 189 12 Transferrin Fusion Protein Therapies: Acetylcholine Receptor-Transferrin Fusion Protein as a Model 191 Dennis Keefe, Michael Heartlein, and Serene Josiah 12.1 Disease Overview, 191 12.2 Fusion Protein SHG2210 Design, 192 12.3 Characterization of SHG2210, 193 12.4 Applications and Indications, 196 12.5 Future Perspectives, 197 12.6 Conclusion, 198 References, 198 13 Half-Life Extension Through O-Glycosylation 201 Fuad Fares 13.1 Introduction, 201 13.2 The Role of O-Linked Oligosaccharide Chains in Glycoprotein Function, 202 13.3 Designing Long-Acting Agonists of Glycoprotein Hormones, 203 13.4 Conclusions, 207 References, 207 14 ELP-Fusion Technology for Biopharmaceuticals 211 Doreen M. Floss, Udo Conrad, Stefan Rose-John, and J urgen Scheller 14.1 Introduction, 211 14.2 ELP-based Protein Purification, 212 14.3 ELPylated Proteins in Medicine and Nanobiotechnology, 215 14.4 Molecular Pharming: a New Application for ELPylation, 217 14.5 Challenges and Future Perspectives, 221 14.6 Conclusion, 222 References, 222 15 Ligand-Receptor Fusion Dimers 227 Sarbendra L. Pradhananga, Ian R. Wilkinson, Eric Ferrandis, Peter J. Artymiuk, Jon R. Sayers, and Richard J. Ross 15.1 Introduction, 227 15.2 The GHLR-Fusions, 228 15.3 Expression and Purification, 229 15.4 Analysis of the LR-Fusions, 229 15.5 LR-Fusions: The Next Generation in Hormone Treatment, 234 15.6 Conclusion, 234 References, 234 16 Development of Latent Cytokine Fusion Proteins 237 Lisa Mullen, Gill Adams, Rewas Fatah, David Gould, Anne Rigby, Michelle Sclanders, Apostolos Koutsokeras, Gayatri Mittal, Sandrine Vessillier, and Yuti Chernajovsky 16.1 Introduction, 237 16.2 Description of Concept, 238 16.3 Limitations of the Latent Cytokine Technology, 240 16.4 Generation of Latent Cytokines, 242 16.5 Applications and Potential Clinical Indications, 244 16.6 Alternatives/Variants of Approach, 246 16.7 Challenges (Production and Development), 247 16.8 Conclusions and Future Perspectives, 248 Acknowledgments, 249 References, 249 IIB TOXIN: CYTOTOXIC FUSION PROTEINS 253 17 Fusion Proteins with Toxic Activity 253 Stefan R. Schmidt 17.1 Introduction, 253 17.2 Toxins, 254 17.3 Immunocytokines, 258 17.4 Human Enzymes, 259 17.5 Apoptosis Induction, 261 17.6 Fc-Based Toxicity, 263 17.7 Peptide-Based Toxicity, 264 17.8 Conclusions and Future Perspectives, 265 References, 265 18 Classic Immunotoxins with Plant or Microbial Toxins 271 Jung Hee Woo and Arthur Frankel 18.1 Introduction, 271 18.2 Toxins Used in Immunotoxin Preparation, 272 18.3 Immunotoxin Design and Synthesis, 274 18.4 Clinical Update of Immunotoxin Trials, 278 18.5 Challenges and Perspective of Classic Immunotoxins, 284 18.6 Conclusions, 286 References, 286 19 Targeted and Untargeted Fusion Proteins: Current Approaches to Cancer Immunotherapy 295 Leslie A. Khawli, Peisheng Hu, and Alan L. Epstein 19.1 Introduction, 295 19.2 Immunotherapeutic Strategy for Cancer: Fusion Proteins, 296 19.3 Immunotherapeutic Applications of Antibody-Targeted and Untargeted Fc Fusion Proteins, 297 19.4 Combination Fusion Proteins Therapy, 305 19.5 Mechanism of Action: Immunoregulatory T-Cell (Treg) Depletion and Fusion Protein Combination Therapy, 306 19.6 Future Directions, 309 19.7 Conclusion, 309 Acknowledgments, 310 References, 310 20 Development of Experimental Targeted Toxin Therapies for Malignant Glioma 315 Nikolai G. Rainov and Volkmar Heidecke 20.1 Introduction, 315 20.2 Targeted Toxins General Considerations, 316 20.3 Delivery Mode and Pharmacokinetics of Targeted Toxins in the Brain, 316 20.4 Preclinical and Clinical Studies with Targeted Toxins, 318 20.5 Conclusions and Future Developments of Targeted Toxins, 324 Disclosure, 325 References, 325 21 Immunokinases 329 Stefan Barth, Stefan Gattenl ohner, and Mehmet Kemal Tur 21.1 Introduction, 329 21.2 Protein Kinases, Apoptosis, and Cancer, 330 21.3 Therapeutic Strategies to Restore Missing Kinase Expression, 331 21.4 Analysis of Immunokinase Efficacy, 333 21.5 Outlook, 334 References, 334 22 ImmunoRNase Fusions 337 Wojciech Ardelt 22.1 Introduction, 337 22.2 Development of ImmunoRNase Fusion Proteins as Biopharmaceuticals, 339 22.3 Aspects of ImmunoRNase Design and Production, 344 22.4 Alternatives, 346 22.5 Conclusions and Future Perspectives, 347 References, 347 23 Antibody-Directed Enzyme Prodrug Therapy (ADEPT) 355 Surinder K. Sharma 23.1 Introduction, 355 23.2 The Components, 355 23.3 ADEPT Systems with Carboxypeptidase G2 (CPG2), 357 23.4 Fusion Proteins, 359 23.5 Immunogenicity, 360 23.6 Conclusions and Future Outlook, 361 Acknowledgments, 361 References, 361 24 Tumor-Targeted Superantigens 365 Gunnar Hedlund, G oran Forsberg, Thore Nederman, Anette Sundstedt, Leif Dahlberg, Mikael Tiensuu, and Mats Nilsson 24.1 Introduction: Tumor-Targeted Superantigens AUnique Concept of Cancer Treatment, 365 24.2 Structure and Production of Tumor-Targeted Superantigens, 366 24.3 Tumor-Targeted Superantigens are Powerful Targeted Immune Activators and Useful for all Types of Malignancies, 367 24.4 Increasing the Therapeutic Window and Exposure by the Creation of a Novel TTS Fusion Protein with Minimal MHC Class II Affinity; Naptumomab Estafenatox, 370 24.5 Clinical Experience with TTS Therapeutic Fusion Proteins, 371 24.6 Combining TTS with Cytostatic and Immunomodulating Anticancer Drugs, 377 24.7 Conclusions, 379 References, 379 IIC TARGETING: FUSION PROTEINS ADDRESSING SPECIFIC CELLS, ORGANS, AND TISSUES 383 25 Fusion Proteins with a Targeting Function 383 Stefan R. Schmidt 25.1 Introduction, 383 25.2 Targeting Organs, 383 25.3 Intracellular Delivery, 388 25.4 Oral Delivery, 391 25.5 Conclusions and Future Perspectives, 392 References, 393 26 Cell-Penetrating Peptide Fusion Proteins 397 Andres Mu~noz-Alarcon, Henrik Helmfors, Kristin Karlsson, and U lo Langel 26.1 Introduction, 397 26.2 Typical Applications and Indications, 397 26.3 Technological Aspects, 399 26.4 Successes and Failures in Preclinical and Clinical Research, 402 26.5 Alternatives/Variants of This Approach, 405 26.6 Conclusions and Future Perspectives, 405 Acknowledgments, 406 References, 406 27 Cell-Specific Targeting of Fusion Proteins through Heparin Binding 413 Jiajing Wang, Zhenzhong Ma, and Jeffrey A. Loeb 27.1 Why Target Heparan-Sulfate Proteoglycans with Fusion Proteins?, 413 27.2 Heparan Sulfate Structure and Biosynthesis Create Diversity and a Template for Targeting Specificity, 415 27.3 Tissue-Specific Expression of HSPGs and the Enzymes That Modify Them, 416 27.4 Heparin-Binding Proteins and Growth Factors, 416 27.5 Viruses Target Cells Through Heparin Binding, 417 27.6 Dissecting Heparin-Binding Protein Domains for Tissue-Specific Targeting, 418 27.7 Fusion Proteins Incorporating HBDs, 418 27.8 The Neuregulin 1 Growth Factor Has a Unique and Highly Specific HBD, 419 27.9 Using Neuregulin s HBD to Generate a Targeted Neuregulin Antagonist, 419 27.10 Tissue Targeting and Therapeutic Efficacy of a Heparin-Targeted NRG1 Antagonist Fusion Protein, 420 27.11 Conclusions and Future Perspectives, 423 References, 424 28 Bone-Targeted Alkaline Phosphatase 429 Jose Luis Millan 28.1 Detailed Description of the Concept, 429 28.2 Technical Aspects, 430 28.3 Applications and Indications, 432 28.4 Preclinical and Clinical Research, 433 28.5 Alternatives/Variants of This Approach, 434 28.6 Challenges in Production and Development, 436 28.7 Conclusions and Future Perspectives, 436 Acknowledgments, 437 References, 437 29 Targeting Interferon-a to the Liver: Apolipoprotein A-I as a Scaffold for Protein Delivery 441 Jessica Fioravanti, Jesus Prieto, and Pedro Berraondo 29.1 Detailed Description of the Concept, 441 29.2 Technological Aspects, 447 29.3 Typical Applications and Indications, 447 29.4 Alternatives and Variants of This Approach, 448 29.5 Conclusions and Future Perspectives, 448 References, 448 PART III BEYOND THE TRIPLE T-PARADIGM 453 IIIA NOVEL CONCEPTS, NOVEL SCAFFOLDS 455 30 Signal Converter Proteins 455 Mark L. Tykocinski 30.1 Introduction, 455 30.2 Historical Roots of Signal Conversion: Artificial Veto Cell Engineering and Protein Painting, 455 30.3 Trans Signal Converter Proteins, 458 30.4 Expanding Trans Signal Conversion Options: Redirecting Signals, 459 30.5 From Trans to Cis Signal Conversion: Driving Auto-Signaling, 460 30.6 Mechanistic Dividends of Chimerization, 461 30.7 Targeting Multiple Diseases with Individual Signal Converters, 462 30.8 Structural Constraints in SCP Design, 463 30.9 Coding SCP Functional Repertoires, 463 30.10 Expanding the Catalog of Inhibitory SCP, 464 30.11 Immune Activating SCP, 466 30.12 Experimental Tools for Screening SCP Candidates, 467 30.13 SCP Frontiers: Mining the Surface Protein Interactome, Rewiring Cellular Networks, 467 References, 468 31 Soluble T-Cell Antigen Receptors 475 Peter R. Rhode 31.1 Soluble T-cell Antigen Receptor (STAR) Fusion Technology and Utilities, 475 31.2 Expression and Purification of Recombinant Star Fusion Proteins, 477 31.3 Clinical and Research Product Applications, 478 31.4 Preclinical Testing Using Star Fusion Proteins, 481 31.5 Clinical Development of ALT-801, 487 31.6 Alternatives/Variants of This Approach, 488 31.7 Challenges, 489 31.8 Conclusions and Future Perspectives, 490 Acknowledgments, 490 References, 490 32 High-Affinity Monoclonal T-Cell Receptor (mTCR) Fusions 495 Nikolai M. Lissin, Namir J. Hassan, and Bent K. Jakobsen 32.1 Introduction: The T Cell Receptor (TCR) as a Targeting Molecule, 495 32.2 Engineered High-Affinity Monoclonal TCRs (mTCR), 497 32.3 mTCR-Based Fusion Proteins for Therapeutic Applications, 500 32.4 Immune-Mobilizing Monoclonal TCRs Against Cancer (ImmTAC), 500 32.5 Conclusions and Future Perspectives, 503 Acknowledgments, 504 References, 504 33 Amediplase 507 Stefano Evangelista and Stefano Manzini 33.1 Introduction, 507 33.2 Source, Physico-Chemical Properties and Formulation, 508 33.3 Preclinical Studies, 510 33.4 Human Studies, 512 33.5 Historical Comparison with Other Thrombolytics, 517 33.6 Conclusions and Future Perspectives, 517 Acknowledgment, 517 References, 517 34 Breaking New Therapeutic Grounds: Fusion Proteins of Darpins and Other Nonantibody Binding Proteins 519 Hans Kaspar Binz 34.1 Introduction, 519 34.2 Novel Scaffolds Alternatives to Antibodies, 519 34.3 New Therapeutic Concepts with Nonantibody Binding Proteins, 523 34.4 Scaffold-Fusion Proteins Beyond Antibody Possibilities, 525 Acknowledgments, 526 References, 526 IIIB MULTIFUNCTIONAL ANTIBODIES 529 35 Resurgence of Bispecific Antibodies 529 Patrick A. Baeuerle and Tobias Raum 35.1 A Brief History of Bispecific Antibodies, 529 35.2 Asymmetric IgG-Like Bispecific Antibodies, 530 35.3 Symmetric IgG-Like Bispecific Antibodies, 531 35.4 IgG-Like Bispecific Antibodies with Fused Antibody Fragments, 533 35.5 Bispecific Constructs Based on the Fcg Fragment, 534 35.6 Bispecific Constructs Based on Fab Fragments, 535 35.7 Bispecific Constructs Based on Diabodies or Single-Chain Antibodies, 536 35.8 Bifunctional Fusions of Antibodies or Fragments with Other Proteins, 538 35.9 Bispecific Antibodies for Various Functions: How to Select the Right Format?, 539 References, 541 36 Novel Applications of Bispecific DART1 Proteins 545 Syd Johnson, Bhaswati Barat, Hua W. Li, Ralph F. Alderson, Paul A. Moore, and Ezio Bonvini 36.1 Introduction, 545 36.2 DART1 Proteins, 546 36.3 Application of DART1 to Cross-Link Inhibitory and Activating Receptors, 546 36.4 Application of Bispecific Antibodies in Oncology, 547 36.5 U-DART Concept for Screening DART1 Candidate Targets and mAbs, 549 36.6 U-DART Concept for Applications in Autoimmune and Inflammatory Disease, 549 36.7 Conclusions and Future Perspectives, 554 References, 554 37 Strand Exchange Engineered Domain (Seed): A Novel Platform Designed to Generate Mono and Multispecific Protein Therapeutics 557 Alec W. Gross, Jessica P. Dawson, Marco Muda, Christie Kelton, Sean D. McKenna, and Bjorn Hock 37.1 Introduction, 557 37.2 Technical Aspects, 558 37.3 Potential Therapeutic Applications, 562 37.4 Future Perspectives, 566 37.5 Conclusions, 567 Acknowledgments, 567 References, 567 38 CovX-Bodies 571 Abhijit Bhat, Olivier Laurent, and Rodney Lappe 38.1 The CovX-Body Concept, 571 38.2 Technological Aspects, 571 38.3 Applications of the CovX-Body Technology, 578 References, 581 39 Modular Antibody Engineering: Antigen Binding Immunoglobulin Fc CH3 Domains as Building Blocks for Bispecific Antibodies (mAb2) 583 Maximilian Woisetschl ager, Florian R uker, Geert C. Mudde, Gordana Wozniak-Knopp, Anton Bauer, and Gottfried Himmler 39.1 Introduction, 583 39.2 Immunoglobulin Fc as a Scaffold, 583 39.3 Design of Libraries Based on the Human IgG1 CH3 Domain, 584 39.4 TNF-a-Binding Fcab: Selection and Characterization of Fcab TNF353-2, 585 39.5 Conclusions and Future Perspectives, 588 Acknowledgments, 588 References, 589 40 Designer Fusion Modules for Building Multifunctional, Multivalent Antibodies, and Immunoconjugates: The Dock-and-Lock Method 591 Edmund A. Rossi, David M. Goldenberg, and Chien-Hsing Chang 40.1 Introduction, 591 40.2 DDD/AD Modules Based on PKA and AKAP, 592 40.3 Advantages and Disadvantages of the DNL Method, 592 40.4 Fab-Based Modules, 593 40.5 IgG-AD2-Modules, 594 40.6 Hexavalent Antibodies, 595 40.7 More Antibody-Based-Modules and Multivalent Antibodies, 596 40.8 Nonantibody-Based DNL Modules, 597 40.9 IFN-a2b-DDD2 Module and Immunocytokines, 597 40.10 Variations on the DNLTheme, 598 40.11 Conclusions and Future Perspective, 599 References, 599 INDEX 603

Product Details

  • ISBN13: 9780470646274
  • Format: Hardback
  • Number Of Pages: 672
  • ID: 9780470646274
  • weight: 2002
  • ISBN10: 0470646276

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