Special Issue "Modes of Antibody Action for Cancer Therapy"

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

Deadline for manuscript submissions: closed (31 March 2013)

Special Issue Editor

Guest Editor
Prof. Dr. Patrick A. Baeuerle

AMGEN Research (Munich) GmbH, Staffelseestr. 2, 81477 Munich, Germany
E-Mail
Interests: bispecific antibodies; T cells; antibody drug conjugates; Fc-engineered antibodies; cancer therapy; antibody targets

Special Issue Information

Dear Colleagues,

Antibody-based therapies have high potential to treat malignant diseases. Very different modes of action can be employed to this end. There are intrinsic properties of antibodies such as ADCC, which can be enhanced by Fc gamma engineering, CDC, or an anti-apoptotic activity induced by antibody binding to a specific target antigen. There are also ways of bolting onto antibodies toxic compounds for improving efficacy. Conjugation of antibodies with plant or bacterial toxins leads to immunotoxins, with chemotherapeutics to antibody drug conjugates (ADCs), and with radioisotopes to radioimmunoconjugates. Bispecific antibodies have the potential to inhibit at a time two receptors, neutralize two angiogenic factors, or combinations thereof. Bispecific antibodies can also be used to tether T cells to cancer target cells, which is not possible with conventional antibodies. Lastly, antibodies binding to immune regulatory receptors can significantly  support natural or antibody-mediated immune reactions against tumors. For each class, there are now drug candidates under late-stage development, or on the market. A special issues with focus on "modes of antibody action against cancer" will review recent developments and allow comparison of these different modes of action.

Prof. Dr. Patrick A. Baeuerle
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibodies is an international peer-reviewed Open Access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 300 CHF (Swiss Francs). English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.

Keywords

  • antibody-dependent cellular cytotoxicity (ADCC)
  • complement-dependent cytotoxicity (CDC)
  • antibody drug conjugates
  • immunotoxins
  • immunocytokines
  • radioimmuno conjugates
  • Fc gamma engineering
  • bispecific antibodies
  • T or NK cell engaging antibodies
  • immune-stimulating antibodies

Published Papers (8 papers)

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Research

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Open AccessArticle CD20 mAb-Mediated Complement Dependent Cytotoxicity of Tumor Cells is Enhanced by Blocking the Action of Factor I
Antibodies 2013, 2(4), 598-616; doi:10.3390/antib2040598
Received: 30 August 2013 / Revised: 13 November 2013 / Accepted: 21 November 2013 / Published: 28 November 2013
Cited by 4 | PDF Full-text (430 KB) | HTML Full-text | XML Full-text
Abstract
The CD20 mAbs, rituximab (RTX) and ofatumumab (OFA), have been used with success in the clinic in the treatment of B cell malignancies. These mAbs can eliminate B cells only by utilizing the body’s immune effector mechanisms, and there is considerable evidence that
[...] Read more.
The CD20 mAbs, rituximab (RTX) and ofatumumab (OFA), have been used with success in the clinic in the treatment of B cell malignancies. These mAbs can eliminate B cells only by utilizing the body’s immune effector mechanisms, and there is considerable evidence that OFA is particularly effective at eliminating B cells by mediating complement dependent cytotoxicity (CDC). However, effector mechanisms such as complement can be exhausted or down-regulated. Therefore, several approaches are being investigated with the goal of increasing CDC mediated by these mAbs. We reported that when patients with chronic lymphocytic leukemia (CLL) are treated with RTX or with OFA, complement is rapidly activated on circulating, targeted CLL B cells. However, a substantial fraction of these cells escape CDC and clearance due to degradation of covalently deposited active C3b fragments to inactive fragments iC3b and C3d. This process is mediated by a plasma protease, Factor I. Therefore, a rational approach for increasing CDC would be to block this reaction by inhibiting Factor I with a neutralizing mAb. Indeed, we have demonstrated that use of neutralizing mAb A247, specific for factor I, significantly and substantially increases CD20 mAb-mediated CDC of both cell lines and of primary CLL cells in vitro. Full article
(This article belongs to the Special Issue Modes of Antibody Action for Cancer Therapy)

Review

Jump to: Research

Open AccessReview Antibody Glycosylation and Inflammation
Antibodies 2013, 2(3), 392-414; doi:10.3390/antib2030392
Received: 3 April 2013 / Revised: 11 June 2013 / Accepted: 18 June 2013 / Published: 25 June 2013
Cited by 18 | PDF Full-text (275 KB) | HTML Full-text | XML Full-text
Abstract
IgG antibodies are the basis of some of the most effective therapeutics developed over the last 20 years. These antibodies are highly specific, have long serum-half lives, and can be produced relatively routinely, making them ideal drugs for immunotherapy. The degree of regulation
[...] Read more.
IgG antibodies are the basis of some of the most effective therapeutics developed over the last 20 years. These antibodies are highly specific, have long serum-half lives, and can be produced relatively routinely, making them ideal drugs for immunotherapy. The degree of regulation on IgG antibody effector functions by the composition of the single, N-linked glycan attached to the Fc is increasingly appreciated. IgG antibodies with identical protein sequences can gain a 50-fold potency, in terms of initiating antibody-dependent cellular cytotoxicity (ADCC) by removal of the single fucose residue from the Fc glycan. Conversely, the addition of sialic acid to the terminus of the Fc glycan converts IgG antibodies into anti-inflammatory mediators, capable of suppressing autoantibody driven inflammation. This review will discuss the contribution of the Fc glycan to IgG antibody effector functions, the regulation of the antibody glycosylation in vivo, implications for the rational design of IgG antibody-based therapeutics, and touch upon the contribution of glycosylation to other immunoglobulin isotypes. Full article
(This article belongs to the Special Issue Modes of Antibody Action for Cancer Therapy)
Open AccessReview Role and Redirection of IgE against Cancer
Antibodies 2013, 2(2), 371-391; doi:10.3390/antib2020371
Received: 4 April 2013 / Revised: 13 May 2013 / Accepted: 14 May 2013 / Published: 28 May 2013
Cited by 1 | PDF Full-text (299 KB) | HTML Full-text | XML Full-text
Abstract
IgE is a highly elusive antibody class, yet a tremendously powerful elicitor of immune reactions. Despite huge efforts spent on the characterization and understanding of the IgE system many questions remain either unanswered or only marginally addressed. One above all relates to the
[...] Read more.
IgE is a highly elusive antibody class, yet a tremendously powerful elicitor of immune reactions. Despite huge efforts spent on the characterization and understanding of the IgE system many questions remain either unanswered or only marginally addressed. One above all relates to the role of IgE. A common doubt is based on whether IgE mode of action should only be relegated to anti-parasite immunity and allergic manifestations. In search for a hidden role of IgE, reports from several laboratories are described herein in which a natural IgE link to cancer or the experimental redirection of IgE against cancer have been investigated. Epidemiological and investigational studies are trying to elucidate a possible direct intervention of endogenous IgE against cancer, raising thus far no definitive evidence. Conversely, experimental approaches implementing several strategies and engineered IgE formats built up a series of convincing results indicating that cancer might be tackled by the effector functions of this immunoglobulin class. Because of its peculiar immune features, IgE may present a superior anti-tumor performance as compared to IgG. However, extreme care should be taken on how IgE-based anti-tumor approaches should be devised. Overall, IgE appears as a promising resource, likely destined to enrich the anti-cancer arsenal. Full article
(This article belongs to the Special Issue Modes of Antibody Action for Cancer Therapy)
Open AccessReview Current and Potential Uses of Immunocytokines as Cancer Immunotherapy
Antibodies 2012, 1(2), 149-171; doi:10.3390/antib1020149
Received: 13 June 2012 / Revised: 26 June 2012 / Accepted: 26 June 2012 / Published: 4 July 2012
Cited by 12 | PDF Full-text (507 KB) | HTML Full-text | XML Full-text
Abstract
Immunocytokines (ICs) are a class of molecules created by linking tumor-reactive monoclonal antibodies to cytokines that are able to activate immune cells. Tumor selective localization is provided by the ability of the mAb component to bind to molecules found on the tumor cell
[...] Read more.
Immunocytokines (ICs) are a class of molecules created by linking tumor-reactive monoclonal antibodies to cytokines that are able to activate immune cells. Tumor selective localization is provided by the ability of the mAb component to bind to molecules found on the tumor cell surface or molecules found selectively in the tumor microenvronment. In this way the cytokine component of the immunocytokine is selectively localized to sites of tumor and can activate immune cells with appropriate receptors for the cytokine. Immunocytokines have been made and tested by us, and others, using a variety of tumor-reactive mAbs linked to distinct cytokines. To date, the majority of clinical progress has been made with ICs that have linked human interleukin-2 (IL2) to a select number of tumor reactive mAbs that had already been in prior clinical testing as non-modified mAbs. Here we briefly review the background for the creation of ICs, summarize current clinical progress, emphasize mechanisms of action for ICs that are distinct from those of their constituent components, and present some directions for future development and testing. Full article
(This article belongs to the Special Issue Modes of Antibody Action for Cancer Therapy)
Open AccessReview Alpha Particle Emitter Radiolabeled Antibody for Metastatic Cancer: What Can We Learn from Heavy Ion Beam Radiobiology?
Antibodies 2012, 1(2), 124-148; doi:10.3390/antib1020124
Received: 3 May 2012 / Revised: 17 June 2012 / Accepted: 20 June 2012 / Published: 26 June 2012
Cited by 1 | PDF Full-text (350 KB) | HTML Full-text | XML Full-text
Abstract
Alpha-particle emitter labeled monoclonal antibodies are being actively developed for treatment of metastatic cancer due to the high linear energy transfer (LET) and the resulting greater biological efficacy of alpha-emitters. Our knowledge of high LET particle radiobiology derives primarily from accelerated heavy ion
[...] Read more.
Alpha-particle emitter labeled monoclonal antibodies are being actively developed for treatment of metastatic cancer due to the high linear energy transfer (LET) and the resulting greater biological efficacy of alpha-emitters. Our knowledge of high LET particle radiobiology derives primarily from accelerated heavy ion beam studies. In heavy ion beam therapy of loco-regional tumors, the modulation of steep transition to very high LET peak as the particle approaches the end of its track (known as the Bragg peak) enables greater delivery of biologically potent radiation to the deep seated tumors while sparing normal tissues surrounding the tumor with the relatively low LET track segment part of the heavy ion beam. Moreover, fractionation of the heavy ion beam can further enhance the peak-to-plateau relative biological effectiveness (RBE) ratio. In contrast, internally delivered alpha particle radiopharmaceutical therapy lack the control of Bragg peak energy deposition and the dose rate is determined by the administered activity, alpha-emitter half-life and biological kinetics of the radiopharmaceutical. The therapeutic ratio of tumor to normal tissue is mainly achieved by tumor specific targeting of the carrier antibody. In this brief overview, we review the radiobiology of high LET radiations learned from ion beam studies and identify the features that are also applicable for the development of alpha-emitter labeled antibodies. The molecular mechanisms underlying DNA double strand break repair response to high LET radiation are also discussed. Full article
(This article belongs to the Special Issue Modes of Antibody Action for Cancer Therapy)
Open AccessReview Natural Killer (NK)- and T-Cell Engaging Antibody-Derived Therapeutics
Antibodies 2012, 1(1), 88-123; doi:10.3390/antib1010088
Received: 19 April 2012 / Revised: 21 May 2012 / Accepted: 24 May 2012 / Published: 1 June 2012
Cited by 2 | PDF Full-text (518 KB) | HTML Full-text | XML Full-text
Abstract
Unmodified antibodies (abs) have been successful in the treatment of hematologic malignancies, but less so for the treatment of solid tumors. They trigger anti-tumor effects through their Fc-domains, and one way to improve their efficacy is to optimize their interaction with the effectors
[...] Read more.
Unmodified antibodies (abs) have been successful in the treatment of hematologic malignancies, but less so for the treatment of solid tumors. They trigger anti-tumor effects through their Fc-domains, and one way to improve their efficacy is to optimize their interaction with the effectors through Fc-engineering. Another way to empower abs is the design of bispecific abs and related fusion proteins allowing a narrower choice of effector cells. Here we review frequently chosen classes of effector cells, as well as common trigger molecules. Natural Killer (NK)- and T-cells are the most investigated populations in therapeutical approaches with bispecific agents until now. Catumaxomab, the first bispecific ab to receive drug approval, targets the tumor antigen Epithelial Cell Adhesion Molecule (EpCAM) and recruits T-cells via a binding site for the cell surface protein CD3. The next generation of recombinant ab-derivatives replaces the broadly reactive Fc-domain by a binding domain for a single selected trigger. Blinatumomab is the first clinically successful member of this class, targeting cancer cells via CD19 and engaging T-cells by CD3. Other investigators have developed related recombinant fusion proteins to recruit effectors, such as NK-cells and macrophages. The first such agents currently in preclinical and clinical development will be discussed. Full article
(This article belongs to the Special Issue Modes of Antibody Action for Cancer Therapy)
Open AccessReview Immunocytokines
Antibodies 2012, 1(1), 70-87; doi:10.3390/antib1010070
Received: 27 April 2012 / Revised: 15 May 2012 / Accepted: 17 May 2012 / Published: 31 May 2012
Cited by 4 | PDF Full-text (311 KB) | HTML Full-text | XML Full-text
Abstract
A number of cytokines have shown beneficial effects in preclinical animal models of cancer and chronic inflammatory diseases. However, cytokine treatment is often associated with severe side effects, which prevent the administration of clinically relevant doses in humans. Immunocytokines are a novel class
[...] Read more.
A number of cytokines have shown beneficial effects in preclinical animal models of cancer and chronic inflammatory diseases. However, cytokine treatment is often associated with severe side effects, which prevent the administration of clinically relevant doses in humans. Immunocytokines are a novel class of biopharmaceuticals, consisting of a cytokine moiety fused to monoclonal antibodies or to an antibody fragment, which selectively accumulate at the disease site and thereby enhance the therapeutic effects of cytokines. This review surveys the recent preclinical and clinical advances in the field, with a special focus on the impact of antibody formats, target antigen and cytokine moieties on the therapeutic performance in vivo. We also discuss emerging data about the possibility to combine immunocytokines with other pharmacological agents. Full article
(This article belongs to the Special Issue Modes of Antibody Action for Cancer Therapy)
Open AccessReview Antibody-Based Immunotoxins for the Treatment of Cancer
Antibodies 2012, 1(1), 39-69; doi:10.3390/antib1010039
Received: 28 March 2012 / Revised: 1 May 2012 / Accepted: 8 May 2012 / Published: 15 May 2012
Cited by 14 | PDF Full-text (1096 KB) | HTML Full-text | XML Full-text
Abstract
Antibody-based immunotoxins comprise an important group in targeted cancer therapeutics. These chimeric proteins are a form of biological guided missiles that combine a targeting moiety with a potent effector molecule. The targeting moiety is mostly a monoclonal antibody (MAb) or a recombinant antibody-based
[...] Read more.
Antibody-based immunotoxins comprise an important group in targeted cancer therapeutics. These chimeric proteins are a form of biological guided missiles that combine a targeting moiety with a potent effector molecule. The targeting moiety is mostly a monoclonal antibody (MAb) or a recombinant antibody-based fragment that confers target specificity to the immunotoxin. The effector domain is a potent protein toxin of bacterial or plant origin, which, following binding to the target cells, undergoes internalization and causes cell death. Over time and following research progression, immunotoxins become better fitted to their purpose, losing immunogenic fragments and non-specific targeting moieties. Many immunotoxins have gone through clinical evaluation. Some of these have been shown to be active and work is progressing with them in the form of further clinical trials. Others, mostly developed in the previous century, failed to generate a response in patients, or even caused undesired side effects. This article reviews the antibody and protein-toxin based immunotoxins that were clinically evaluated up to the present day. Full article
(This article belongs to the Special Issue Modes of Antibody Action for Cancer Therapy)

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Type of Paper: Review
Title: IgG Effector Function Dictated by the Fc Glycan Composition
Authors: Kai-Ting Chuang and Robert M. Anthony
Affiliation: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA
Abstract: IgG antibodies are the basis for some of the most effective therapeutics developed over the last 20 years. These proteins are highly specific, have long serum-half lives, and can be produced relatively routinely, making them ideal drugs. Importantly, the effector functions that are elicited by IgG antibodies can be enhanced or manipulated by the composition of the single, N-linked glycan attached to the Fc. IgG antibodies with identical protein sequences can gain 50- fold increased potency, in terms of initiating antibody-dependent cytotoxicity, by removing a single, specific sugar moiety from the Fc glycan. Conversely, the addition of sialic acid to the terminus of the Fc glycan converts IgG antibodies into anti-inflammatory mediators, capable of suppressing autoantibody driven inflammation. This review will discuss the contribution of the Fc glycan to IgG antibody effector functions, the regulation of the Fc glycan in vivo, and implications for the rationale design of IgG antibody-based therapeutics.

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