Polymer-Protein Conjugates

From Pegylation and Beyond

Gianfranco Pasut, Samuel Zalipsky

• Publisher: Elsevier
• Year: 2019
• Print ISBN: 9780444640819
• eBook ISBN: 9780444640826
• Topic: Technology & Engineering
• Subtopic: Chemical & Biochemical Engineering
• Index: Technology & Engineering

Polymer–Protein Conjugates: From Pegylation and Beyond helps researchers by offering a unique reference and guide into this fascinating area. Sections cover the challenges surrounding the homogeneity of conjugates, their purity and polymer toxicity on long-term use, and how to deal with the risk of immunogenicity. These discussions help researchers design new projects by taking into account the latest innovations for safe and site selective polymer conjugation to proteins. PEG has been the gold standard and likely will play this role for many years, but alternatives are coming into the market, some of which have already been launched.After five decades of improvements, the ideas in this book are entering into a new era of innovation because of the advances in genetic engineering, biochemistry and a better understanding of the results from clinical use of PEG conjugates in humans.- Provides an overview on the state-of-the-art of protein polymer conjugation- Presents both the pros and cons of polymer-protein conjugates from the point-of-view of their clinical outcomes- Outlines advantages and potential risks of present technology based on PEG- Offers new alternatives for PEG and new approaches for on site-selective protein modification- Identifies future direction of research in this field

Part 1

Introduction and general aspects of the technology

Outline

1. Evolution of polymer conjugation to proteins

2. PEGylated proteins: A rational design for mitigating clearance mechanisms and altering biodistribution

3. Overcoming barriers for tumor-targeted drug delivery: the power of macromolecular anticancer drugs with the EPR effect and the modulation of vascular physiology

1

Evolution of polymer conjugation to proteins

Samuel Zalipsky¹, and Gianfranco Pasut^{2 1}Independent Consultant, Redwood City, CA, United States ²Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy

Abstract

The purpose of this chapter is to provide proper perspective on the field of polymer conjugates with therapeutic proteins, including a brief overview on how the field developed and where it is headed, as well as how the content of this book fits in this overall picture. The realm of therapeutic protein–polymer conjugates emerged now as a mature yet vibrant field with continuous improvements in methods and applications. The number of new conjugate approvals has never been as high as in the recent years, and this, together with the wave of first biosimilars of Neulasta, has brought an increased attention to this area of research with many new companies entering the field of polymer conjugation. Multiple review articles and a few books were previously published on various aspects of the art (Torchilin, 1987; Lee, 1991; Harris and Zalipsky, 1997; Veronese, 2009; Duncan and Kopecek, 1984; Veronese and Pasut, 2005; Pasut and Veronese, 2012; Zalipsky, 1995) Here we are not attempting to be comprehensive, but to cover some significant developments and trends.

Keywords

PEGylation; Polymer conjugation; Protein delivery

1. Inspiration and rational of this book

The inspiration for this book sparked after a recent meeting of the editors. We are both considered experts in the field of polymer conjugation but we have not had the opportunity to work together before. In an informal chat, we agreeably discussed this technology from the early days to the recent achievements going through the great successes and some pitfalls. We recall the names of the researchers (F.F. Davis, F.M. Veronese, J.M. Harris, A. Sehon, E. Akerbloom, J. Kopecek, R. Duncan, V. Torchilin) who greatly contributed to the progress of this technology from both the academia and industry side. As the conversation was going on, we agreed that something was missing in the present literature on protein–polymer conjugation. Although many reviews have been published on various aspects of polymer–protein conjugates, we concluded that a review alone, as good it may be, typically narrowly focuses and does not do justice to the whole field and also the previous overviews were not up to date [1–8]. To well represent the technology, to thoroughly discuss the marketed products, to analyze the recent achievements, to objectively review the potential safety issues, and to discuss the future perspectives, a book was needed to refresh and update the state of this field—a book that, starting from the state of the art, offers the best knowhow for the development of future conjugates that can guide and help both the researchers entering the field and those already working in it to further advance without repeating the previous mistakes, a book that takes into consideration the recent concerns about the safety profile of the most used polymer in this field, polyethylene glycol (PEG), with a detailed discussion that can help and reassure the decision-makers about their choices. The process from the first envisioning of this book to its materialization was a long development, and the final product became possible mainly thanks to the great dedication and expertise of all our outstanding contributors.

2. Book content and its significance

The book has been organized as a balanced collection of contributions from authors belonging to academia and industry. Although PEGylation is the most discussed topic, owing to the undoubted success of PEG and its many clinically approved conjugates, there are chapters dedicated to potential PEG alternatives that are in preclinical or clinical investigation such as polysaccharides, see the contributions of Ferguson et al. (Chapter 19) and Turecek et al. (Chapter 20), polyoxazolines by Hoogenboom et al. (Chapter 18), and also new architecturally/functionally complex polymers by Gauthier et al. (Chapter 17). In the biopolymer field, there is a continuity of new approaches; a complete report of this field is beyond the scope of the book, so only some of the most relevant contributions are covered. From the side of conjugation chemistry, the random coupling to lysine residues—i.e., amine-directed conjugation—has been already extensively reviewed [4,6–10]. In this volume, description of this methodology can be found within the chapters on the development of products that reached the clinical approval or are in advanced stages of clinical investigation. Conversely, dedicated chapters are dealing with site-specific approaches, including thiol-directed conjugation at genetically engineered cysteines by Katre et al. (Chapter 14), bisalkylation by Brocchini et al. (Chapter 16), conjugation at noncanonical amino acids by Winblade Nairn et al. (Chapter 15), glycan-directed PEGylation by Lederkremer et al. (Chapter 11), glycan enzymatic conjugation by Behrens et al. (Chapter 12), and enzyme-mediated approaches of polymer conjugation by Pasut et al. (Chapter 13). A considerable part of the book is dedicated to contributions from pharma companies on the development of their product candidates. This is covered by the following contributions: Winblade Nairn (Allozyne; Chapter 15), Bossard (Nektar; Chapters 2 and 7), Nock (Teva; Chapter 6), Maneval (Halozyme; Chapter 9), Brandenburg (Medac; Chapter 10), Turecek (Takeda; Chapters 4, 8 and 20), and Behrens (Novo Nordisk; Chapter 12). Furthermore, Vicent and Bossard (Chapter 2) contributed an overview on how PEGylation has been applied to overcome the issues of biotech drugs, such as immunogenicity and fast body clearance. On the issue of potential safety risks of poly...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedications
• Contributors
• Foreword
• My journey with PEGylation
• Part 1. Introduction and general aspects of the technology
• Part 2. Toxicity and immunogenicity studies and clinical stage conjugate products
• Part 3. Novel site-selective methods of conjugation
• Part 4. Alternative non-PEG polymers and architectures
• PEGylation and polymer conjugation
• Index