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. 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. PREFACE xxiii CONTRIBUTORS xxv PART I INTRODUCTION 1 1 Fusion Proteins: Applications and Challenges 3 Stefan R. Schmidt References, 18 2 Analyzing and Forecasting the Fusion Protein Market and Pipeline 25 Mark Belsey and Giles Somers Disclaimer, 36 Acknowledgment, 36 References, 36 3 Structural Aspects of Fusion Proteins Determining the Level of Commercial Success 39 Giles Somers References, 54 4 Fusion Protein Linkers: Effects on Production, Bioactivity, and Pharmacokinetics 57 Xiaoying Chen, Jennica Zaro, and Wei-Chiang Shen References, 71 5 Immunogenicity of Therapeutic Fusion Proteins: Contributory Factors and Clinical Experience 75 Vibha Jawa, Leslie Cousens, and Anne S. De Groot 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 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 References, 118 8 Peptide-Fc Fusion Therapeutics: Applications and Challenges 123 Chichi Huang and Ronald V. Swanson 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 Acknowledgment, 155 References, 155 10 Recombinant Albumin Fusion Proteins 163 Thomas Weimer, Hubert J. Metzner, and Stefan Schulte 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 References, 189 12 Transferrin Fusion Protein Therapies: Acetylcholine Receptor-Transferrin Fusion Protein as a Model 191 Dennis Keefe, Michael Heartlein, and Serene Josiah References, 198 13 Half-Life Extension Through O-Glycosylation 201 Fuad Fares References, 207 14 ELP-Fusion Technology for Biopharmaceuticals 211 Doreen M. Floss, Udo Conrad, Stefan Rose-John, and JEURurgen Scheller 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 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 Acknowledgments, 249 References, 249 IIB TOXIN: CYTOTOXIC FUSION PROTEINS 253 17 Fusion Proteins with Toxic Activity 253 Stefan R. Schmidt References, 265 18 Classic Immunotoxins with Plant or Microbial Toxins 271 Jung Hee Woo and Arthur Frankel References, 286 19 Targeted and Untargeted Fusion Proteins: Current Approaches to Cancer Immunotherapy 295 Leslie A. Khawli, Peisheng Hu, and Alan L. Epstein Acknowledgments, 310 References, 310 20 Development of Experimental Targeted Toxin Therapies for Malignant Glioma 315 Nikolai G. Rainov and Volkmar Heidecke Disclosure, 325 References, 325 21 Immunokinases 329 Stefan Barth, Stefan GattenlEURohner, and Mehmet Kemal Tur References, 334 22 ImmunoRNase Fusions 337 Wojciech Ardelt References, 347 23 Antibody-Directed Enzyme Prodrug Therapy (ADEPT) 355 Surinder K. Sharma Acknowledgments, 361 References, 361 24 Tumor-Targeted Superantigens 365 Gunnar Hedlund, GEURoran Forsberg, Thore Nederman, Anette Sundstedt, Leif Dahlberg, Mikael Tiensuu, and Mats Nilsson References, 379 IIC TARGETING: FUSION PROTEINS ADDRESSING SPECIFIC CELLS, ORGANS, AND TISSUES 383 25 Fusion Proteins with a Targeting Function 383 Stefan R. Schmidt References, 393 26 Cell-Penetrating Peptide Fusion Proteins 397 Andres Mu~noz-Alarcon, Henrik Helmfors, Kristin Karlsson, and EURU lo Langel Acknowledgments, 406 References, 406 27 Cell-Specific Targeting of Fusion Proteins through Heparin Binding 413 Jiajing Wang, Zhenzhong Ma, and Jeffrey A. Loeb References, 424 28 Bone-Targeted Alkaline Phosphatase 429 Jose Luis Millan 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 References, 448 PART III BEYOND THE TRIPLE T-PARADIGM 453 IIIA NOVEL CONCEPTS, NOVEL SCAFFOLDS 455 30 Signal Converter Proteins 455 Mark L. Tykocinski References, 468 31 Soluble T-Cell Antigen Receptors 475 Peter R. Rhode Acknowledgments, 490 References, 490 32 High-Affinity Monoclonal T-Cell Receptor (mTCR) Fusions 495 Nikolai M. Lissin, Namir J. Hassan, and Bent K. Jakobsen Acknowledgments, 504 References, 504 33 Amediplase 507 Stefano Evangelista and Stefano Manzini Acknowledgment, 517 References, 517 34 Breaking New Therapeutic Grounds: Fusion Proteins of Darpins and Other Nonantibody Binding Proteins 519 Hans Kaspar Binz Acknowledgments, 526 References, 526 IIIB MULTIFUNCTIONAL ANTIBODIES 529 35 Resurgence of Bispecific Antibodies 529 Patrick A. Baeuerle and Tobias Raum 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 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 Bjrn Hock Acknowledgments, 567 References, 567 38 CovX-Bodies 571 Abhijit Bhat, Olivier Laurent, and Rodney Lappe References, 581 39 Modular Antibody Engineering: Antigen Binding Immunoglobulin Fc CH3 Domains as Building Blocks for Bispecific Antibodies (mAb2) 583 Maximilian WoisetschlEURager, Florian REURuker, Geert C. Mudde, Gordana Wozniak-Knopp, Anton Bauer, and Gottfried Himmler 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 References, 599 INDEX 603
