Antibody Engineering for Cancer Immunotherapy

A special issue of Antibodies (ISSN 2073-4468).

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 119047

Special Issue Editors

St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King’s College London, Guy’s Hospital, London SE1 9RT, UK
Interests: melanoma; antibody–drug conjugate; antibody targeted therapy; cancer immunology; immunotherapy; antibody engineering and glycoengineering; B cells
Special Issues, Collections and Topics in MDPI journals
Translational Cancer Immunology and Immunotherapy, St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London SE1 9RT, UK
Interests: B cell responses in cancer; antibody engineering and glycoengineering; IgE class of antibodies in cancer; antibody Fc-mediated functions in cancer; cancer immunology; cancer immunotherapy; antibody-drug conjugates; melanoma; ovarian cancer; breast cancer; allergo-oncology; ADCC; ADCP; macrophages; monocytes; NK cells
Special Issues, Collections and Topics in MDPI journals
Department of Translational Science, UCB Pharma, 208 Bath Road, Slough SL1 3WE, UK
Interests: immunotherapy; therapeutic antibodies; antibody isotypes; antibody engineering; T-cells; myeloid cells; NK cells; B cells; cancer immunology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Since Rituximab, the first chimeric monoclonal antibody approved for the treatment of non-Hodgkin lymphoma in the late nineties, antibody engineering for cancer immunotherapy has become a rapidly growing field, with more than 30 antibody therapeutics approved in the US and EU and hundreds in clinical trial.

Among the engineered antibodies approved so far, there are chimeric antibodies, humanized antibodies, Fc-engineered antibodies, antibody fragments, and one bispecific antibody.

The field of antibody engineering spans across many areas: from antibody variable region humanisation to Fc engineering, isotype optimization, and antibody glyco-engineering; from antibody–drug conjugates to immuno-cytokines; and from antibody fragments to the bi- and multispecific antibodies and cell engagers who have been leading the field in the last decade.

This Special Issue on "Antibody Engineering for Cancer Immunotherapy" aims to provide an up-to-date overview of the growing field of antibody engineering, including novel strategies for antibody humanisation, Fc engineering, alternative isotype selection, antibody glyco-engineering, antibody–drug conjugates, immuno-cytokines, antibody fragments, bi- and multispecific antibodies and cell engagers.

We look forward to receiving your original article or review submission to this Special Issue of Antibodies.

Dr. Silvia Crescioli
Prof. Sophia Karagiannis
Dr. Ann White
Guest Editors

Manuscript Submission Information

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Keywords

  • Antibody engineering
  • Cancer immunotherapy
  • Bi-specific antibodies
  • Multispecific antibodies
  • Fc engineering
  • T-cell engagers
  • Antibody humanisation
  • Antibody glycoengineering

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Published Papers (11 papers)

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Editorial

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3 pages, 161 KiB  
Editorial
Special Issue “Antibody Engineering for Cancer Immunotherapy”
Antibodies 2022, 11(2), 29; https://doi.org/10.3390/antib11020029 - 15 Apr 2022
Cited by 1 | Viewed by 2590
Abstract
Since the approval of Rituximab in the late 1990s, the first chimeric monoclonal antibody for the treatment of non-Hodgkin lymphoma, antibody engineering for cancer immunotherapy has become a rapidly growing field, with almost 50 antibody therapeutics approved in the USA and EU and [...] Read more.
Since the approval of Rituximab in the late 1990s, the first chimeric monoclonal antibody for the treatment of non-Hodgkin lymphoma, antibody engineering for cancer immunotherapy has become a rapidly growing field, with almost 50 antibody therapeutics approved in the USA and EU and hundreds undergoing testing in clinical trials [...] Full article
(This article belongs to the Special Issue Antibody Engineering for Cancer Immunotherapy)

Research

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21 pages, 4975 KiB  
Article
Molecular Mechanism of HER2 Rapid Internalization and Redirected Trafficking Induced by Anti-HER2 Biparatopic Antibody
Antibodies 2020, 9(3), 49; https://doi.org/10.3390/antib9030049 - 18 Sep 2020
Cited by 18 | Viewed by 10460
Abstract
Amplification and overexpression of HER2 (human epidermal growth factor receptor 2), an ErbB2 receptor tyrosine kinase, have been implicated in human cancer and metastasis. A bispecific tetravalent anti-HER2 antibody (anti-HER2-Bs), targeting two non-overlapping epitopes on HER2 in domain IV (trastuzumab) and domain II [...] Read more.
Amplification and overexpression of HER2 (human epidermal growth factor receptor 2), an ErbB2 receptor tyrosine kinase, have been implicated in human cancer and metastasis. A bispecific tetravalent anti-HER2 antibody (anti-HER2-Bs), targeting two non-overlapping epitopes on HER2 in domain IV (trastuzumab) and domain II (39S), has been reported to induce rapid internalization and efficient degradation of HER2 receptors. In this study, we investigated the molecular mechanism of this antibody-induced rapid HER2 internalization and intracellular trafficking. Using quantitative fluorescent imaging, we compared the internalization kinetics of anti-HER2-Bs and its parental arm antibodies, alone or in combinations and under various internalization-promoting conditions. The results demonstrated that concurrent engagement of both epitopes was necessary for rapid anti-HER2-Bs internalization. Cellular uptake of anti-HER2-Bs and parental arm antibodies occurred via clathrin-dependent endocytosis; however, inside the cells antibodies directed different trafficking pathways. Trastuzumab dissociated from HER2 in 2 h, enabling the receptor to recycle, whereas anti-HER2-Bs stayed associated with the receptor throughout the entire endocytic pathway, promoting receptor ubiquitination, trafficking to the lysosomes, and efficient degradation. Consistent with routing HER2 to degradation, anti-HER2-Bs significantly reduced HER2 shedding and altered its exosomal export. Collectively, these results enable a better understanding of the mechanism of action of anti-Her2-Bs and can guide the rational design of anti-HER2 therapeutics as well as other bispecific molecules. Full article
(This article belongs to the Special Issue Antibody Engineering for Cancer Immunotherapy)
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10 pages, 5293 KiB  
Article
Rapid Isolation of Rare Isotype-Switched Hybridoma Variants: Application to the Generation of IgG2a and IgG2b MAb to CD63, a Late Endosome and Exosome Marker
Antibodies 2020, 9(3), 29; https://doi.org/10.3390/antib9030029 - 02 Jul 2020
Cited by 4 | Viewed by 4388
Abstract
CD63, a member of the tetraspanin superfamily, is used as a marker of late endosomes and lysosome-related organelles, as well as a marker of exosomes. Here, we selected rare isotype variants of TS63 by sorting hybridoma cells on the basis of their high [...] Read more.
CD63, a member of the tetraspanin superfamily, is used as a marker of late endosomes and lysosome-related organelles, as well as a marker of exosomes. Here, we selected rare isotype variants of TS63 by sorting hybridoma cells on the basis of their high expression of surface immunoglobulins of the IgG2a and IgG2b subclass. Pure populations of cells secreting IgG2a and IgG2b variants of TS63 (referred to as TS63a and TS63b) were obtained using two rounds of cell sorting and one limited dilution cloning step. We validate that these new TS63 variants are suitable for co-labeling with mAb of the IgG1 subclass directed to other molecules, using anti mouse subclass antibodies, and for the labeling of exosomes through direct binding to protein A-coated gold particles. These mAbs will be useful to study the intracellular localization of various proteins and facilitate electron microscopy analysis of CD63 localization. Full article
(This article belongs to the Special Issue Antibody Engineering for Cancer Immunotherapy)
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Review

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20 pages, 1971 KiB  
Review
Glycoengineering of Therapeutic Antibodies with Small Molecule Inhibitors
Antibodies 2021, 10(4), 44; https://doi.org/10.3390/antib10040044 - 04 Nov 2021
Cited by 8 | Viewed by 7039
Abstract
Monoclonal antibodies (mAbs) are one of the cornerstones of modern medicine, across an increasing range of therapeutic areas. All therapeutic mAbs are glycoproteins, i.e., their polypeptide chain is decorated with glycans, oligosaccharides of extraordinary structural diversity. The presence, absence, and composition of these [...] Read more.
Monoclonal antibodies (mAbs) are one of the cornerstones of modern medicine, across an increasing range of therapeutic areas. All therapeutic mAbs are glycoproteins, i.e., their polypeptide chain is decorated with glycans, oligosaccharides of extraordinary structural diversity. The presence, absence, and composition of these glycans can have a profound effect on the pharmacodynamic and pharmacokinetic profile of individual mAbs. Approaches for the glycoengineering of therapeutic mAbs—the manipulation and optimisation of mAb glycan structures—are therefore of great interest from a technological, therapeutic, and regulatory perspective. In this review, we provide a brief introduction to the effects of glycosylation on the biological and pharmacological functions of the five classes of immunoglobulins (IgG, IgE, IgA, IgM and IgD) that form the backbone of all current clinical and experimental mAbs, including an overview of common mAb expression systems. We review selected examples for the use of small molecule inhibitors of glycan biosynthesis for mAb glycoengineering, we discuss the potential advantages and challenges of this approach, and we outline potential future applications. The main aim of the review is to showcase the expanding chemical toolbox that is becoming available for mAb glycoengineering to the biology and biotechnology community. Full article
(This article belongs to the Special Issue Antibody Engineering for Cancer Immunotherapy)
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36 pages, 3900 KiB  
Review
Importance and Considerations of Antibody Engineering in Antibody-Drug Conjugates Development from a Clinical Pharmacologist’s Perspective
Antibodies 2021, 10(3), 30; https://doi.org/10.3390/antib10030030 - 26 Jul 2021
Cited by 12 | Viewed by 8696
Abstract
Antibody-drug conjugates (ADCs) appear to be in a developmental boom, with five FDA approvals in the last two years and a projected market value of over $4 billion by 2024. Major advancements in the engineering of these novel cytotoxic drug carriers have provided [...] Read more.
Antibody-drug conjugates (ADCs) appear to be in a developmental boom, with five FDA approvals in the last two years and a projected market value of over $4 billion by 2024. Major advancements in the engineering of these novel cytotoxic drug carriers have provided a few early success stories. Although the use of these immunoconjugate agents are still in their infancy, valuable lessons in the engineering of these agents have been learned from both preclinical and clinical failures. It is essential to appreciate how the various mechanisms used to engineer changes in ADCs can alter the complex pharmacology of these agents and allow the ADCs to navigate the modern-day therapeutic challenges within oncology. This review provides a global overview of ADC characteristics which can be engineered to alter the interaction with the immune system, pharmacokinetic and pharmacodynamic profiles, and therapeutic index of ADCs. In addition, this review will highlight some of the engineering approaches being explored in the creation of the next generation of ADCs. Full article
(This article belongs to the Special Issue Antibody Engineering for Cancer Immunotherapy)
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26 pages, 2756 KiB  
Review
Recent Advances in the Molecular Design and Applications of Multispecific Biotherapeutics
Antibodies 2021, 10(2), 13; https://doi.org/10.3390/antib10020013 - 30 Mar 2021
Cited by 22 | Viewed by 9337
Abstract
Recombinant protein-based biotherapeutics drugs have transformed clinical pipelines of the biopharmaceutical industry since the launch of recombinant insulin nearly four decades ago. These biologic drugs are structurally more complex than small molecules, and yet share a similar principle for rational drug discovery and [...] Read more.
Recombinant protein-based biotherapeutics drugs have transformed clinical pipelines of the biopharmaceutical industry since the launch of recombinant insulin nearly four decades ago. These biologic drugs are structurally more complex than small molecules, and yet share a similar principle for rational drug discovery and development: That is to start with a pre-defined target and follow with the functional modulation with a therapeutic agent. Despite these tremendous successes, this “one target one drug” paradigm has been challenged by complex disease mechanisms that involve multiple pathways and demand new therapeutic routes. A rapidly evolving wave of multispecific biotherapeutics is coming into focus. These new therapeutic drugs are able to engage two or more protein targets via distinct binding interfaces with or without the chemical conjugation to large or small molecules. They possess the potential to not only address disease intricacy but also exploit new therapeutic mechanisms and assess undruggable targets for conventional monospecific biologics. This review focuses on the recent advances in molecular design and applications of major classes of multispecific biotherapeutics drugs, which include immune cells engagers, antibody-drug conjugates, multispecific tetherbodies, biologic matchmakers, and small-scaffold multispecific modalities. Challenges posed by the multispecific biotherapeutics drugs and their future outlooks are also discussed. Full article
(This article belongs to the Special Issue Antibody Engineering for Cancer Immunotherapy)
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23 pages, 770 KiB  
Review
Utilizing Immunocytokines for Cancer Therapy
Antibodies 2021, 10(1), 10; https://doi.org/10.3390/antib10010010 - 09 Mar 2021
Cited by 19 | Viewed by 7247
Abstract
Cytokine therapy for cancer has indicated efficacy in certain diseases but is generally accompanied by severe toxicity. The field of antibody–cytokine fusion proteins (immunocytokines) arose to target these effector molecules to the tumor environment in order to expand the therapeutic window of cytokine [...] Read more.
Cytokine therapy for cancer has indicated efficacy in certain diseases but is generally accompanied by severe toxicity. The field of antibody–cytokine fusion proteins (immunocytokines) arose to target these effector molecules to the tumor environment in order to expand the therapeutic window of cytokine therapy. Pre-clinical evidence has shown the increased efficacy and decreased toxicity of various immunocytokines when compared to their cognate unconjugated cytokine. These anti-tumor properties are markedly enhanced when combined with other treatments such as chemotherapy, radiotherapy, and checkpoint inhibitor antibodies. Clinical trials that have continued to explore the potential of these biologics for cancer therapy have been conducted. This review covers the in vitro, in vivo, and clinical evidence for the application of immunocytokines in immuno-oncology. Full article
(This article belongs to the Special Issue Antibody Engineering for Cancer Immunotherapy)
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15 pages, 711 KiB  
Review
Fc Engineering Strategies to Advance IgA Antibodies as Therapeutic Agents
Antibodies 2020, 9(4), 70; https://doi.org/10.3390/antib9040070 - 15 Dec 2020
Cited by 25 | Viewed by 7380
Abstract
In the past three decades, a great interest has arisen in the use of immunoglobulins as therapeutic agents. In particular, since the approval of the first monoclonal antibody Rituximab for B cell malignancies, the progress in the antibody-related therapeutic agents has been incremental. [...] Read more.
In the past three decades, a great interest has arisen in the use of immunoglobulins as therapeutic agents. In particular, since the approval of the first monoclonal antibody Rituximab for B cell malignancies, the progress in the antibody-related therapeutic agents has been incremental. Therapeutic antibodies can be applied in a variety of diseases, ranging from cancer to autoimmunity and allergy. All current therapeutic monoclonal antibodies used in the clinic are of the IgG isotype. IgG antibodies can induce the killing of cancer cells by growth inhibition, apoptosis induction, complement activation (CDC) or antibody-dependent cellular cytotoxicity (ADCC) by NK cells, antibody-dependent cellular phagocytosis (ADCP) by monocytes/macrophages, or trogoptosis by granulocytes. To enhance these effector mechanisms of IgG, protein and glyco-engineering has been successfully applied. As an alternative to IgG, antibodies of the IgA isotype have been shown to be very effective in tumor eradication. Using the IgA-specific receptor FcαRI expressed on myeloid cells, IgA antibodies show superior tumor-killing compared to IgG when granulocytes are employed. However, reasons why IgA has not been introduced in the clinic yet can be found in the intrinsic properties of IgA posing several technical limitations: (1) IgA is challenging to produce and purify, (2) IgA shows a very heterogeneous glycosylation profile, and (3) IgA has a relatively short serum half-life. Next to the technical challenges, pre-clinical evaluation of IgA efficacy in vivo is not straightforward as mice do not naturally express the FcαR. Here, we provide a concise overview of the latest insights in these engineering strategies overcoming technical limitations of IgA as a therapeutic antibody: developability, heterogeneity, and short half-life. In addition, alternative approaches using IgA/IgG hybrid and FcαR-engagers and the impact of engineering on the clinical application of IgA will be discussed. Full article
(This article belongs to the Special Issue Antibody Engineering for Cancer Immunotherapy)
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34 pages, 3590 KiB  
Review
Fc-Engineering for Modulated Effector Functions—Improving Antibodies for Cancer Treatment
Antibodies 2020, 9(4), 64; https://doi.org/10.3390/antib9040064 - 17 Nov 2020
Cited by 91 | Viewed by 20383
Abstract
The majority of monoclonal antibody (mAb) therapeutics possess the ability to engage innate immune effectors through interactions mediated by their fragment crystallizable (Fc) domain. By delivering Fc-Fc gamma receptor (FcγR) and Fc-C1q interactions, mAb are able to link exquisite specificity to powerful cellular [...] Read more.
The majority of monoclonal antibody (mAb) therapeutics possess the ability to engage innate immune effectors through interactions mediated by their fragment crystallizable (Fc) domain. By delivering Fc-Fc gamma receptor (FcγR) and Fc-C1q interactions, mAb are able to link exquisite specificity to powerful cellular and complement-mediated effector functions. Fc interactions can also facilitate enhanced target clustering to evoke potent receptor signaling. These observations have driven decades-long research to delineate the properties within the Fc that elicit these various activities, identifying key amino acid residues and elucidating the important role of glycosylation. They have also fostered a growing interest in Fc-engineering whereby this knowledge is exploited to modulate Fc effector function to suit specific mechanisms of action and therapeutic purposes. In this review, we document the insight that has been generated through the study of the Fc domain; revealing the underpinning structure-function relationships and how the Fc has been engineered to produce an increasing number of antibodies that are appearing in the clinic with augmented abilities to treat cancer. Full article
(This article belongs to the Special Issue Antibody Engineering for Cancer Immunotherapy)
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27 pages, 2734 KiB  
Review
IgE Antibodies against Cancer: Efficacy and Safety
Antibodies 2020, 9(4), 55; https://doi.org/10.3390/antib9040055 - 16 Oct 2020
Cited by 18 | Viewed by 8684
Abstract
Immunoglobulin E (IgE) antibodies are well known for their role in allergic diseases and for contributions to antiparasitic immune responses. Properties of this antibody class that mediate powerful effector functions may be redirected for the treatment of solid tumours. This has led to [...] Read more.
Immunoglobulin E (IgE) antibodies are well known for their role in allergic diseases and for contributions to antiparasitic immune responses. Properties of this antibody class that mediate powerful effector functions may be redirected for the treatment of solid tumours. This has led to the rise of a new class of therapeutic antibodies to complement the armamentarium of approved tumour targeting antibodies, which to date are all IgG class. The perceived risk of type I hypersensitivity reactions following administration of IgE has necessitated particular consideration in the development of these therapeutic agents. Here, we bring together the properties of IgE antibodies pivotal to the hypothesis for superior antitumour activity compared to IgG, observations of in vitro and in vivo efficacy and mechanisms of action, and a focus on the safety considerations for this novel class of therapeutic agent. These include in vitro studies of potential hypersensitivity, selection of and observations from appropriate in vivo animal models and possible implications of the high degree of glycosylation of IgE. We also discuss the use of ex vivo predictive and monitoring clinical tools, as well as the risk mitigation steps employed in, and the preliminary outcomes from, the first-in-human clinical trial of a candidate anticancer IgE therapeutic. Full article
(This article belongs to the Special Issue Antibody Engineering for Cancer Immunotherapy)
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20 pages, 1095 KiB  
Review
Monoclonal Antibodies in Cancer Therapy
Antibodies 2020, 9(3), 34; https://doi.org/10.3390/antib9030034 - 20 Jul 2020
Cited by 306 | Viewed by 31057
Abstract
Monoclonal antibody-based immunotherapy is now considered to be a main component of cancer therapy, alongside surgery, radiation, and chemotherapy. Monoclonal antibodies possess a diverse set of clinically relevant mechanisms of action. In addition, antibodies can directly target tumor cells while simultaneously promoting the [...] Read more.
Monoclonal antibody-based immunotherapy is now considered to be a main component of cancer therapy, alongside surgery, radiation, and chemotherapy. Monoclonal antibodies possess a diverse set of clinically relevant mechanisms of action. In addition, antibodies can directly target tumor cells while simultaneously promoting the induction of long-lasting anti-tumor immune responses. The multifaceted properties of antibodies as a therapeutic platform have led to the development of new cancer treatment strategies that will have major impacts on cancer care. This review focuses on the known mechanisms of action, current clinical applications for the treatment of cancer, and mechanisms of resistance of monoclonal antibody therapy. We further discuss how monoclonal antibody-based strategies have moved towards enhancing anti-tumor immune responses by targeting immune cells instead of tumor antigens as well as some of the current combination therapies. Full article
(This article belongs to the Special Issue Antibody Engineering for Cancer Immunotherapy)
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