Therapeutic Antibody Engineering: Current And Future Advances Driving The Strongest Growth Area In T
Kirby Apodaca
Chapters 9 through 11 review the various antibody classes and the optimization of Fc function to improve their performance. The majority of the 75 antibodies and Fc-fusion proteins on the market or in advanced clinical trials are based on natural IgG1 molecules. Other isotypes are underutilized and, interestingly, are surpassed in number by molecules with an engineered Fc. This indicates the high importance of antibodies with optimized Fc function or pharmacology for the generation of novel, more potent therapies. Antibody format improvements through protein or glycoengineering are reviewed in detail and their applicability discussed. Future antibody innovation challenges include the potential to harness the advantages of IgM and IgA antibodies in terms of valency, potency and mucosal surface delivery, as well as further antibody format optimization to allow the targeting of specific tissues. Although these approaches still lack clinical validation, they provide strong opportunities for the generation of more effective future antibody therapeutics.
Therapeutic Antibody Engineering: Current And Future Advances Driving The Strongest Growth Area In T
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Chapter 12 reviews therapeutic antibody fragments. While the first antibody fragment approved for human use was a Fab fragment with a novel mechanism of action, the development of therapeutic molecules in this class has thereafter been limited to differentiated follow-ons, such as fragments targeting tumor necrosis factor or vascular endothelial growth factor. Dr. Strohl clearly summarizes the strategic reasons that form the basis of a decision to develop an antibody fragment rather than a whole antibody. These include target-product profiles, which require a short half-life, absence of effector function, monovalency or the potential as an engineering scaffold. Approaches to extend half-life of molecules in this class are also discussed.
Chapter 13 discusses both polyclonal antibody approaches and engineered multispecific molecules. This seems like a non-obvious choice because the former approach encompassing serum therapies and intravenous immunoglobulin is traditional and conservative. In fact, the new defined polyclonal mixtures can be considered extensions taught by the classical intravenous immunoglobulin concept. Engineered multispecific antibodies, by comparison, are novel entities that emerged from appreciating the polypharmacology of many human diseases. In this respect, the classification of multispecific antibodies by their intended mechanism of action, instead of their molecular structures, might have been more straightforward. Indeed, bispecific recruiter antibodies, such as BITEs, TandAbs, and MM-111 share many challenges with early antibody-drug conjugates, whereas dual-ligand or receptor blockers should be compared with antibody mixtures. Given this heterogeneity, the statement of potentially lower therapeutic indexes for multispecific antibodies (e.g., due to partially overlapping minimally effective and maximally tolerated concentrations of the respective separate entities) seems too general. A better understanding of the pharmacology of multispecific antibodies clearly represents a critical area of future study.
Antibody-drug conjugates arguably represent one of the fastest therapeutic antibody growth areas. Chapter 15 discusses target, antibody scaffold, linker and toxin selection, which are all critical for optimal antibody-drug conjugate activity, as well as lessons learned and focus areas for future exploration.
It has been more than three decades since the first monoclonal antibody was approved by the United States Food and Drug Administration (US FDA) in 1986, and during this time, antibody engineering has dramatically evolved. Current antibody drugs have increasingly fewer adverse effects due to their high specificity. As a result, therapeutic antibodies have become the predominant class of new drugs developed in recent years. Over the past five years, antibodies have become the best-selling drugs in the pharmaceutical market, and in 2018, eight of the top ten bestselling drugs worldwide were biologics. The global therapeutic monoclonal antibody market was valued at approximately US$115.2 billion in 2018 and is expected to generate revenue of $150 billion by the end of 2019 and $300 billion by 2025. Thus, the market for therapeutic antibody drugs has experienced explosive growth as new drugs have been approved for treating various human diseases, including many cancers, autoimmune, metabolic and infectious diseases. As of December 2019, 79 therapeutic mAbs have been approved by the US FDA, but there is still significant growth potential. This review summarizes the latest market trends and outlines the preeminent antibody engineering technologies used in the development of therapeutic antibody drugs, such as humanization of monoclonal antibodies, phage display, the human antibody mouse, single B cell antibody technology, and affinity maturation. Finally, future applications and perspectives are also discussed.
Transgenic animals represent another technology for obtaining fully human mAbs (Fig. 3c). This technology was introduced in 1994 by the publication of two transgenic mouse lines, the HuMabMouse [35] and the XenoMouse [36]. The lines were genetically modified such that human immunoglobulin (Ig) genes were inserted into the genome, replacing the endogenous Ig genes and making these animals capable of synthesizing fully human antibodies upon immunization [35, 37]. The first human antibody generated in a transgenic mouse to anti-epidermal growth factor receptor (EGFR), panitumumab, was approved by the US FDA in 2006 (Fig. 1) [38, 39]. The number of fully human antibodies made from transgenic mice has increased rapidly, with the number of approved drugs currently at 19 (Table 5). Depending on the immunization protocol, high-affinity human antibodies can be obtained through further selection of hybridoma clones generated from immunized transgenic mice. Using a theoretically similar approach, the generation of neutralizing human antibodies from human B cells has also yielded promising results for infectious disease therapeutics.
The recent development of bispecific antibodies offers attractive new opportunities for the design of novel protein therapeutics. A bispecific antibody can be generated by utilizing protein engineering techniques to link two antigen binding domains (such as Fabs or scFvs), allowing a single antibody to simultaneously bind different antigens. Thus, bispecific antibodies may be engineered to exhibit novel functions, which do not exist in mixtures of the two parental antibodies. Most bispecific antibodies are designed to recruit cytotoxic effector cells of the immune system to target pathogenic cells [40]. The first approved bispecific antibody was catumaxomab in Europe in 2009 [41]. Catumaxomab targets CD3 and EpCAM to treat solid tumors in patients with malignant ascites. However, this drug was withdrawn from the market in 2017 for commercial reasons. Currently, two bispecific antibodies have obtained US FDA approval and are on the market. First, blinatumomab is a bispecific T-cell engager (BiTE) that targets CD3 and CD19 for treatment of B-cell precursor acute lymphoblastic leukemia (ALL) [42]. Second, emicizumab is a full-size bispecific IgG with natural architecture, which binds to activated coagulation factors IX and X for the treatment of haemophilia A [43]. To date, there are more than 85 bispecific antibodies in clinical trials, about 86% of which are under evaluation as cancer therapies [40]. The concepts and platforms driving the development of bispecific antibodies continue to advance rapidly, creating many new opportunities to make major therapeutic breakthroughs.
Twenty-nine novel antibody therapeutics were in late-stage clinical studies for non-cancer indications in 2018. Among the trials for these mAbs, no single therapeutic area predominated, but 40% were for immune-mediated disorders, which comprised the largest group. From this group of potential treatments, leronlimab and brolucizumab entered regulatory review by the end of 2018, and five mAbs (eptinezumab, teprotumumab, crizanlizumab, satralizumab, and tanezumab) may enter regulatory review in 2019. In comparison, there were 33 novel antibody therapeutics in late-stage clinical studies for cancer indications in 2018. Antibody therapeutics for solid tumors clearly predominated, with less than 20% of the candidates intended solely for hematological malignancies. Five mAbs (isatuximab, spartalizumab, tafasitamab, dostarlimab, and ublituximab) license applications were submitted to the US FDA in 2019 [2].
The use of humanized antibodies has helped greatly to improve clinical tolerance of mAb therapeutics. Such intricate control over antibody sequences has opened the door to engineering mAbs for a wide range of possible applications in medicine. Currently, half of all mAbs used to treat humans are chimeric or humanized (Fig. 2, Table 1). One of the most well-known humanized antibodies is Trastuzumab (Herceptin), which was approved in 1998 and achieved annual sales of over $7 billion in 2018 (Table 2). Trastuzumab is used for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer and gastroesophageal junction adenocarcinoma [57, 58].
The field of therapeutic antibodies has undergone rapid growth in recent years, becoming a dominant force in the therapeutics market. However, there is still significant growth potential for the therapeutic antibody field. Traditionally, antibodies have been used for the treatment of cancer, autoimmune diseases, and infectious diseases. If the molecular mechanisms of a specific disease can be clearly elucidated and the specific proteins or molecules involved in pathogenesis can be identified, antibodies may provide an effective therapeutic option. For example, anti-CGRP receptor antibodies (erenumab, galcanezumab, or fremanezumab) have been developed for the prevention of migraine. Anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies (evolocumab or alirocumab) are used for the treatment of hypercholesterolemia. Anti-fibroblast growth factor 23 (FGF23) antibody (burosumab) is used to treat X-linked hypophosphatemia. Anti-IL6R antibody (sarilumab and tocilizumab) can be used for the treatment of rheumatoid arthritis. Anti-Factor IXa/Xa antibody (emicizumab) is a valuable treatment for hemophilia A. Anti-von Willebrand factor antibody (caplacizumab) is approved for the treatment of thrombotic thrombocytopenic purpura, and other antibodies will be approved for new indications in the near future.
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