Cover Page

Methods and Principles in Medicinal Chemistry


Edited by R. Mannhold, G. Folkers, H. Buschmann

Editorial Board

J. Holenz, H. Kubinyi, H. Timmerman, H. van de Waterbeemd, John Bondo Hansen


Previous Volumes of this Series:

Ecker, G. F., Clausen, R. P., and Sitte, H. H. (Eds.)

Transporters as Drug Targets


ISBN: 978-3-527-33384-4

Vol. 70


Martic-Kehl, M. I., Schubiger, P.A. (Eds.)

Animal Models for Human Cancer

Discovery and Development of Novel Therapeutics


ISBN: 978-3-527-33997-6

Vol. 69


Holenz, Jörg (Ed.)

Lead Generation

Methods and Strategies


ISBN: 978-3-527-33329-5

Vol. 68


Erlanson, Daniel A. / Jahnke, Wolfgang (Eds.)

Fragment-based Drug Discovery

Lessons and Outlook


ISBN: 978-3-527-33775-0

Vol. 67


Urbán, László / Patel, Vinod F. / Vaz, Roy J. (Eds.)

Antitargets and Drug Safety


ISBN: 978-3-527-33511-4

Vol. 66


Keserü, György M. / Swinney, David C. (Eds.)

Kinetics and Thermodynamics of Drug Binding


ISBN: 978-3-527-33582-4

Vol. 65


Pfannkuch, Friedlieb / Suter-Dick, Laura (Eds.)

Predictive Toxicology

From Vision to Reality


ISBN: 978-3-527-33608-1

Vol. 64


Kirchmair, Johannes (Ed.)

Drug Metabolism Prediction


ISBN: 978-3-527-33566-4

Vol. 63


Vela, José Miguel / Maldonado, Rafael / Hamon, Michel (Eds.)

In vivo Models for Drug Discovery


ISBN: 978-3-527-33328-8

Vol. 62


Liras, Spiros / Bell, Andrew S. (Eds.)

Phosphodiesterases and Their Inhibitors


ISBN: 978-3-527-33219-9

Vol. 61

Edited by Tristan Vaughan, Jane Osbourn, and Bahija Jallal


Protein Therapeutics


Volume 1






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Edited by Tristan Vaughan, Jane Osbourn, and Bahija Jallal


Protein Therapeutics


Volume 2






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The number of marketed protein therapeutics [1–3] has increased enormously since the introduction of the first recombinant protein, human insulin, into the clinic several decades ago. Protein therapeutics play a very significant role in many various fields of medicine, and their use continues to steadily broaden. There are several key advantages of protein therapeutics over small-molecule drugs that contribute to this [1]:

Many successful uses of protein therapeutics are documented in this volume. However some challenges still remain for the discovery and development of protein therapeutics: (i) The current route of administration is typically parenteral. Development of oral biologics remains largely an aspiration at this time. (ii) Although the production of recombinant proteins is becoming increasingly efficient and cost–effective, it remains relatively expensive compared to that of small molecules. (iii) The body may mount an immune response against the therapeutic protein. In some cases, this immune response can neutralize the protein and reduce the efficacy of the potential drug.

Taken together, the early success of recombinant insulin production in the 1970s created an atmosphere of enthusiasm and hope, which was followed by an era of disappointment when the vaccine attempts, nonhumanized monoclonal antibodies, and cancer trials in the 1980s were largely unsuccessful. Despite these setbacks, significant progress has been made. With the large number of protein therapeutics both in current clinical use and in clinical trials for a range of disorders, one can confidently predict that protein therapeutics will have a further expanding role in future medicine and may – together with cell and gene therapy – dominate over classical therapeutic approaches based on small-molecule drugs.

Accordingly, this is an appropriate time to review our current knowledge and future perspectives of protein therapeutics as realized in this volume by experts in the field both from industry and academia. It is organized in six sections, first of which introduces the past and present development of protein therapeutics in the chapters on “Early Recombinant Protein Therapeutics” and “Evolution of Antibody Therapeutics.” The second section is dedicated to antibodies as the ultimate scaffold for protein therapeutics and is covered in two chapters on “Human Antibody Structure and Function” as well as “Antibodies from Other Species.” Discovery and engineering of protein therapeutics are described in the next section comprising detailed chapters on “Human Antibody Discovery Platforms,” “Beyond Antibodies: Engineered Protein Scaffolds for Therapeutic Development,” “Protein Engineering: Methods and Applications,” “Bispecifics,” and on “Antibody–Drug conjugates.” Physiological and manufacturing considerations are given in the follow-up section including overviews on “Pharmacokinetics,” “Safety Considerations,” “Immunogenicity,” “Expression Systems for Manufacture,” and a chapter on “Stability, Formulation, and Delivery.” The section on Clinical Applications discusses in detail “Protein Therapeutics in Autoimmune and Inflammatory Diseases, Oncology, Respiratory, and Infectious Diseases.” Chapters on “Rescue Therapies” and “Biosimilars” supplement this section. Future horizons and new target class opportunities are the topics of the final section.

The series editors thank Tristan Vaughan, Jane Osbourn, and Bahija Jallal for organizing this volume and for identifying and working with such excellent authors. Last but not least we thank Frank Weinreich and Waltraud Wüst from Wiley-VCH for their valuable contributions to this project and to the entire book series.

May 2017

Raimund Mannhold, Düsseldorf
Gerd Folkers, Zürich
Helmut Buschmann, Aachen


  1. 1 Leader, B., Baca, Q.J., and Golan, D.E. (2008) Protein therapeutics: a summary and pharmacological classification. Nat. Rev. Drug Discov., 7, 21–39.
  2. 2 Tsomaia, N. (2015) Peptide therapeutics: targeting the undruggable space. Eur. J. Med. Chem., 94, 459–470.
  3. 3 Carter, P.J. (2011) Introduction to current and future protein therapeutics: a protein engineering perspective. Exp. Cell Res., 317, 1261–1269.
  4. 4 Reichert, J.M. (2003) Trends in development and approval times for new therapeutics in the United States. Nat. Rev. Drug Discov., 2, 695–702.

A Personal Foreword

To a diabetic patient, it is hard to imagine a world without biosynthetic insulin. For a new parent of a premature baby, Synagis provides potentially life-saving prevention of respiratory syncytial virus. And for someone suffering the devastating effects of rheumatoid arthritis, Humira, the world's first fully human antibody, introduced in 2002, is so effective that it has become the world's best-selling medicine. Today, biologics such as these account for nearly half of all new drug approvals across the globe and nearly 25% of overall sales. In fact, in 2015, 6 biologics were among the top 10 best-selling drugs worldwide. With more than 500 biopharmaceuticals on the market, biologics represent the fastest growing sector of this industry, targeting illnesses such as cancer, asthma, cardiovascular disease, infectious diseases, multiple sclerosis, hepatitis, inflammatory disease, and so many others.

As a student of physiology and biochemistry in Paris, I was struck by the possibility of modifying proteins to increase their potential to treat illness. My postdoctoral work in molecular biology and oncology at the Max-Planck Institute for Biochemistry in Munich allowed me to focus on the analysis of epidermal growth factor receptor (EGF-R and HER2) signaling and to investigate the antitumor properties of the novel secreted tumor-associated antigen 90K.

My later work building the translational sciences function at Sugen further heightened my interest. But the day I met a patient with renal cell carcinoma who was successfully being treated with Sutent, a multitargeted receptor tyrosine kinase (RTK) inhibitor, made me realize that my true calling was to work in the biopharmaceutical industry to discover new drugs to help patients. Today, as the head of MedImmune, the global biologics early research and development unit of AstraZeneca, I am even more excited by the possibilities of using protein therapeutics to not just treat or prevent disease but to provide a durable cure for so many illnesses affecting patients across the globe.

This book dissects the field of protein therapeutics, from its early struggles to its promising future, and provides a thorough look into this dynamic industry. It touches on exciting developments around immuno-therapies for oncology – advancements I never thought were possible in my lifetime. It delves into the considerable energy going into the development of antibody drug conjugates and their potential for new therapies. Other topics include human and nonhuman antibodies; technological advances in protein therapeutics, including human antibody discovery platforms, nonantibody scaffolds and antibody mimetics; protein engineering and physiological and manufacturing considerations around pharmacokinetics, immunogenicity, safety, and manufacturing; and clinical applications for protein therapeutics.

Protein Therapeutics concludes with a view into innovation of the future, including the potential to target protein therapeutics across the blood–brain barrier for the treatment of diseases ranging from brain tumors to Alzheimer's disease and how protein therapeutics could be delivered intracellularly to gain a better understanding of protein interactions and, for example, modify the RAS/MAPK pathway that could be potentially transformative for the treatment of leukemia and other cancers.

With contributions from recognized academic and industry experts, including Professor Pierre De Meyts, the leading academician in the field of insulin research and one of the fathers of protein therapeutics, and Herren Wu, MedImmune's chief technology officer who offers just a glimpse at potential future innovations, Protein Therapeutics will be a valuable addition to a field that is profoundly changing the way we treat disease.

Gaithersburg, MD

December 2016

Bahija Jallal


We would like to express our gratitude to Karen Stanger for her proactive stewardship over early stages of this project and to Fay Larman who helped us see it through to completion. We are, of course, most indebted to all the authors for taking time out from their daily activities to make so many excellent and insightful contributions to this handbook, as well as to all the reviewers for providing valuable critique and comment. Finally, we would like to especially thank all of you, the scientists, who have contributed so much to this most exciting, dynamic, and motivational field. There is nothing more rewarding than having the opportunity to meet a patient who is benefitting from a protein therapeutic that you have had the good fortune to have helped discover and develop.

Part I
Introduction to Protein Therapeutics: Past and Present