Antibodies

Research

Jump to: Review

430 KiB

Open AccessArticle

CD20 mAb-Mediated Complement Dependent Cytotoxicity of Tumor Cells is Enhanced by Blocking the Action of Factor I

by Margaret A. Lindorfer, Paul V. Beum and Ronald P. Taylor

Antibodies 2013, 2(4), 598-616; https://doi.org/10.3390/antib2040598 - 28 Nov 2013

Cited by 13 | Viewed by 8266

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)

► Show Figures

Figure 1

Review

Jump to: Research

275 KiB

Open AccessReview

Antibody Glycosylation and Inflammation

by Kai-Ting C. Shade and Robert M. Anthony

Antibodies 2013, 2(3), 392-414; https://doi.org/10.3390/antib2030392 - 25 Jun 2013

Cited by 92 | Viewed by 35728

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)

► Show Figures

Figure 1

299 KiB

Open AccessReview

Role and Redirection of IgE against Cancer

by Elisa A. Nigro, Antonio G. Siccardi and Luca Vangelista

Antibodies 2013, 2(2), 371-391; https://doi.org/10.3390/antib2020371 - 28 May 2013

Cited by 2 | Viewed by 10132

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)

► Show Figures

Figure 1

507 KiB

Open AccessReview

Current and Potential Uses of Immunocytokines as Cancer Immunotherapy

by Paul M. Sondel and Stephen D. Gillies

Antibodies 2012, 1(2), 149-171; https://doi.org/10.3390/antib1020149 - 4 Jul 2012

Cited by 32 | Viewed by 9957

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)

► Show Figures

Figure 1

350 KiB

Open AccessReview

Alpha Particle Emitter Radiolabeled Antibody for Metastatic Cancer: What Can We Learn from Heavy Ion Beam Radiobiology?

by Hong Song, Srinivasan Senthamizhchelvan, Robert F. Hobbs and George Sgouros

Antibodies 2012, 1(2), 124-148; https://doi.org/10.3390/antib1020124 - 26 Jun 2012

Cited by 16 | Viewed by 11006

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)

► Show Figures

Figure 1

518 KiB

Open AccessReview

Natural Killer (NK)- and T-Cell Engaging Antibody-Derived Therapeutics

by Christoph Stein, Ingo Schubert and Georg H. Fey

Antibodies 2012, 1(1), 88-123; https://doi.org/10.3390/antib1010088 - 1 Jun 2012

Cited by 6 | Viewed by 15971

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)

► Show Figures

Figure 1

311 KiB

Open AccessReview

Immunocytokines

by Katrin L. Gutbrodt and Dario Neri

Antibodies 2012, 1(1), 70-87; https://doi.org/10.3390/antib1010070 - 31 May 2012

Cited by 14 | Viewed by 9989

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)

► Show Figures

Figure 1

1096 KiB

Open AccessReview

Antibody-Based Immunotoxins for the Treatment of Cancer

by Nurit Becker and Itai Benhar

Antibodies 2012, 1(1), 39-69; https://doi.org/10.3390/antib1010039 - 15 May 2012

Cited by 56 | Viewed by 15342

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)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Modes of Antibody Action for Cancer Therapy

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (8 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI