Year : 2012 | Volume
: 135 | Issue : 3 | Page : 444--445
Recombinant antibodies for immunotherapy
NK Mehra, Prashant Sood
Department of Transplant Immunology & Immunogenetics, All India Institute of Medical Sciences, New Delhi 110 029, India
N K Mehra
Department of Transplant Immunology & Immunogenetics, All India Institute of Medical Sciences, New Delhi 110 029
|How to cite this article:|
Mehra N K, Sood P. Recombinant antibodies for immunotherapy.Indian J Med Res 2012;135:444-445
|How to cite this URL:|
Mehra N K, Sood P. Recombinant antibodies for immunotherapy. Indian J Med Res [serial online] 2012 [cited 2020 Jun 5 ];135:444-445
Available from: http://www.ijmr.org.in/text.asp?2012/135/3/444/95645
Recombinant antibodies for immunotherapy, Melvyn Little, editor (Cambridge University Press, Cambridge, UK) 2009. 434 pages. Price: ͳ 80.00
This multi-author treatise by Melvyn Little brings a fresh perspective to the recombinant antibody genre of books. Unlike other textbooks which deliberate upon the intricacies of this field from a protein engineering and cellular immunology perspective, this publication blends the former with its translational applications and their impact on the health care and pharmaceutical industry. The book is sectioned into 10 parts highlighting major aspects of the technology and its usage through 24 lucid chapters written by eminent experts in the field. Each chapter is supported by elaborate illustrations to succinctly deliver concepts and appropriate Tables that summarize trials and data on candidate molecules. While each chapter maintains a translational tone to discuss the proteomics and their clinical applications, the write up retains lucidity for uninitiated readers that include science graduates and young researchers.
Following the initial success of the hybridoma technology, it soon became clear that monoclonal antibodies (mAb) of animal origin may not be effective in the human system in recruiting cellular immune responses and that these may be plagued by attenuation of their biological activity owing to human anti-mouse antibody (HAMA) response. Part 1 of the book largely deliberates upon various technological advances and their impact in overcoming these hurdles. For example, the emergence of humanized mAb, eventually gave way to various new variants like CDR-grafted antibodies, reshaped antibodies, SDR-transfer antibodies, veneered/resurfaced antibodies, and deimmunized antibodies, each of which is aimed at minimizing or eliminating the immunogenicity of engineered molecules. Chapter 1 gives an overview of the various successful molecules based on these technologies currently in clinical use, like renal transplantation (Daclizumab); multiple sclerosis and Crohn's disease (Natalizumab); and rheumatoid arthritis (Tocilizumab). Likewise the immunogenicity assessment of therapeutic antibodies has been covered well in chapter 2. Various factors that drive mAb immunogenicity including aggregate formation, "foreignness", dosing, routes of administration, impurities and immunomodulating conditions have been discussed followed by strategic testing of molecules for anti-drug antibody (ADA) response. These concepts have been explained with prominent examples like alemtuzumab (for rheumatoid arthritis and B-CLL) and rituximab (for B-CLL). Chapter 3 further dissects the immunological intricacies of the immunogenicity process including MHC class II peptide loading followed by T cell receptor binding and activation. The chapter describes the application of in vitro human T cell assays to locate T cell epitopes in the variable regions of therapeutic antibodies and specifically target these epitopes for removal/substitution and deimmunization to scale down or eliminate immunogenicity.
Part II of the book familiarizes the reader with various technologies in vogue for generation and screening of antibody libraries with chapters devoted to protocols for developing antibody libraries from naοve V gene sources, generation and utility of IgM libraries for mAb development, anti-IL-13-receptor antibodies isolated from IgM libraries and a discussion on the recent development of the fully human antibody library known as the Human Combinatorial Antibody Library (HuCAL GOLD) based on phage display of Fab antibody fragments. This section discusses in details various steps involved in the development of antibody libraries right from their design, diversity, size, quality, phage and ribosomal display formats for screening to construction, assembly and cloning of library constituents. Further, the chapter highlights the novel and more superior CsyDisplay, AutoCAL and HuCALAgx technologies which complement and automate HuCAL library screening.
Part III of the book discusses state of the art developments in relation to transgenic human antibody technology with focus on development of therapeutic molecules. Discussion on XenoMouse transgenic technology wherein the mouse antibody machinery is "humanized", paves the way for the generation of high-affinity, potent, fully human mAbs to several antigens, interleukins and growth factors. The best known example is Panitumumab which is a fully human IgG 2κ mAb against EGFR with very high affinity for the EGFR ligands as well as the transforming growth factor alpha. This antibody has demonstrated significant anti-tumour activity and has been shown to eradicate large established tumours when combined with chemotherapy in a xenograft mouse model. Chapter 8 describes the VelocImmune; mouse, created by megabase-scale humanization of the variable portion of the mouse immunoglobulin loci and is among the largest precision genome-engineering project to date.
Parts IV to VIII take the readers through various antibody engineering technologies designed to augment efficiency, reduce immunogenicity and increase the translational pliability of novel therapeutic antibodies and small proteins. Chapter 9 provides an overview of the immunological mechanisms regulating tumour cell killing by therapeutic antibodies and further discusses protein engineering strategies employed to enhance tumour cytotoxic pathways. Chapter 10 extends this discussion by going into the nuances of Fc domain optimization for enhancing antibody effector functions.The authors have discussed the role played by glycoengineering, FcγR profiling, amino acid engineering and "Knockout Fc" technologies in enhancing antibody based therapeutics. Chapter 11 delves into the intricacies of glycoengineered antibodies, which are characterized by engineered polypeptide and/or oligosaccharide components increasing their affinity for FcγRIII and thus their capacity for antibody-dependent cellular cytotoxicity (ADCC).
Chapters 12 to 14 discuss cutting-edge developments in translation of monoclonal antibodies into highly specific carriers of cytotoxic drugs for cancer chemotherapeutics, radio-immune conjugates and antibody fusion proteins for immunotherapeutics. Chapters 15, 16 & 17 take the discussion into novel antibody formats aimed at better control of antibody half-life and therapeutic efficacy. The authors have succinctly discussed mAb variants like single-domain antibodies, single-chain Fv antibodies, diabody constructs, "Flexibodies", non-CDR loop constructs and variable and constant domain fusion proteins. They have further discussed the clinical applications of these products in immunotherapy of several diseases that include rheumatoid arthritis, pathogenic infections, and cancer immunotherapy. In an attempt to construct antibody molecules which can completely evade human immune surveillance, the concept of utilizing non-antibody scaffolds has recently emerged. Chapter 18 analyzes the development, biophysical properties, reduced antigenicity and disadvantages of these novel molecules. These include, bispecific binding molecules, fusion protein immunocytokines, immunoliposomes, "Affibodies", "DARPins", "Monobodies", "Anticalins" and "Avimers". Chapters 19 and 20 describe emerging technologies which are being employed to augment serum half life and improve pharmacokinetics of therapeutic antibodies, including PEGylation and genetic fusion of therapeutic proteins to albumin (immunobumin).
Part IX describes novel innovations in current immunotherapeutic approaches. Chapter 21 talks about merging stem-cell based platforms for discovery and development of anticancer therapeutic antibodies against novel targets. This has been exemplified by the novel Raven mAb/target discovery platform. Chapter 22 describes the ADEPT (antibody directed enzyme prodrug therapy) strategy for cancer chemotherapeutics using mAb to target enzyme-prodrug therapy with high specificity for tumour cells. Finally, chapter 23 closes this section with a discussion on rendering immune tolerance to therapeutic antibodies with a special focus on their cytokine mediated adverse effects. The final chapter of the book familiarizes the readers with the commercial and market perspectives of this rapidly growing pharmaceutical sector, including pricing, patents, role of FDA, antibody companies, and large scale manufacturing. Already a number of very robust and well validated antibodies are in use in clinical practice with visible effect even in developing economies. Today's physician including specialists like rheumatologists, oncologists, nephrologists, gastroenterologists and transplant surgeons have felt the fundamental and beneficial impact of these treatment paradigms in their day-to-day practice. The therapeutic MAbs have to a large extent addressed the unmet medical needs, particularly in cancer therapy.
In summary, this book takes a fresh look at therapeutic antibodies, not only from a protein engineering perspective but also at their translational applications, improvisations, commercial mass production and regulatory policies. The book thus promises to be a useful reference on therapeutic antibodies for students, established scientists and industry experts in antibody engineering alike.