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Antibodies, Volume 7, Issue 1 (March 2018)

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Editorial

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Open AccessEditorial Acknowledgement to Reviewers of Antibodies in 2017
Antibodies 2018, 7(1), 7; https://doi.org/10.3390/antib7010007
Received: 10 January 2018 / Revised: 10 January 2018 / Accepted: 10 January 2018 / Published: 10 January 2018
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Abstract
Peer review is an essential part in the publication process, ensuring that Antibodies maintains high quality standards for its published papers.[...] Full article

Research

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Open AccessFeature PaperArticle Controlling the Glycosylation Profile in mAbs Using Time-Dependent Media Supplementation
Antibodies 2018, 7(1), 1; https://doi.org/10.3390/antib7010001
Received: 16 October 2017 / Revised: 23 November 2017 / Accepted: 15 December 2017 / Published: 21 December 2017
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Abstract
In order to meet desired drug product quality targets, the glycosylation profile of biotherapeutics such as monoclonal antibodies (mAbs) must be maintained consistently during manufacturing. Achieving consistent glycan distribution profiles requires identifying factors that influence glycosylation, and manipulating them appropriately via well-designed control
[...] Read more.
In order to meet desired drug product quality targets, the glycosylation profile of biotherapeutics such as monoclonal antibodies (mAbs) must be maintained consistently during manufacturing. Achieving consistent glycan distribution profiles requires identifying factors that influence glycosylation, and manipulating them appropriately via well-designed control strategies. Now, the cell culture media supplement, MnCl2, is known to alter the glycosylation profile in mAbs generally, but its effect, particularly when introduced at different stages during cell growth, has yet to be investigated and quantified. In this study, we evaluate the effect of time-dependent addition of MnCl2 on the glycan profile quantitatively, using factorial design experiments. Our results show that MnCl2 addition during the lag and exponential phases affects the glycan profile significantly more than stationary phase supplementation does. Also, using a novel computational technique, we identify various combinations of glycan species that are affected by this dynamic media supplementation scheme, and quantify the effects mathematically. Our experiments demonstrate the importance of taking into consideration the time of addition of these trace supplements, not just their concentrations, and our computational analysis provides insight into what supplements to add, when, and how much, in order to induce desired changes. Full article
(This article belongs to the Special Issue Monoclonal Antibodies) Printed Edition available
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Open AccessArticle Tumor-Directed Blockade of CD47 with Bispecific Antibodies Induces Adaptive Antitumor Immunity
Antibodies 2018, 7(1), 3; https://doi.org/10.3390/antib7010003
Received: 30 October 2017 / Revised: 22 December 2017 / Accepted: 22 December 2017 / Published: 3 January 2018
Cited by 1 | PDF Full-text (2032 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
CD47 serves as an anti-phagocytic receptor that is upregulated by cancer to promote immune escape. As such, CD47 is the focus of intense immuno-oncology drug development efforts. However, as CD47 is expressed ubiquitously, clinical development of conventional drugs, e.g., monoclonal antibodies, is confronted
[...] Read more.
CD47 serves as an anti-phagocytic receptor that is upregulated by cancer to promote immune escape. As such, CD47 is the focus of intense immuno-oncology drug development efforts. However, as CD47 is expressed ubiquitously, clinical development of conventional drugs, e.g., monoclonal antibodies, is confronted with patient safety issues and poor pharmacology due to the widespread CD47 “antigen sink”. A potential solution is tumor-directed blockade of CD47, which can be achieved with bispecific antibodies (biAbs). Using mouse CD47-blocking biAbs in a syngeneic tumor model allowed us to evaluate the efficacy of tumor-directed blockade of CD47 in the presence of the CD47 antigen sink and a functional adaptive immune system. We show here that CD47-targeting biAbs inhibited tumor growth in vivo, promoting durable antitumor responses and stimulating CD8+ T cell activation in vitro. In vivo efficacy of the biAbs could be further enhanced when combined with chemotherapy or PD-1/PD-L1 immune checkpoint blockade. We also show that selectivity and pharmacological properties of the biAb are dependent on the affinity of the anti-CD47 arm. Taken together, our study validates the approach to use CD47-blocking biAbs either as a monotherapy or part of a multi-drug approach to enhance antitumor immunity. Full article
(This article belongs to the Special Issue Monoclonal Antibodies) Printed Edition available
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Open AccessArticle In-Depth Comparison of Lysine-Based Antibody-Drug Conjugates Prepared on Solid Support Versus in Solution
Antibodies 2018, 7(1), 6; https://doi.org/10.3390/antib7010006
Received: 15 December 2017 / Revised: 2 January 2018 / Accepted: 4 January 2018 / Published: 7 January 2018
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Abstract
Antibody drug conjugates are a rapidly growing form of targeted chemotherapeutics. As companies and researchers move to develop new antibody–drug conjugate (ADC) candidates, high-throughput methods will become increasingly common. Here we use advanced characterization techniques to assess two trastuzumab-DM1 (T-DM1) ADCs; one produced
[...] Read more.
Antibody drug conjugates are a rapidly growing form of targeted chemotherapeutics. As companies and researchers move to develop new antibody–drug conjugate (ADC) candidates, high-throughput methods will become increasingly common. Here we use advanced characterization techniques to assess two trastuzumab-DM1 (T-DM1) ADCs; one produced using Protein A immobilization and the other produced in solution. Following determination of payload site and distribution with liquid chromatography-mass spectrometry (LC/MS), thermal stability, heat-induced aggregation, tertiary structure, and binding affinity were characterized using differential scanning calorimetry (DSC), dynamic light scattering (DLS), Raman spectroscopy, and isothermal titration calorimetry (ITC), respectively. Small differences in the thermal stability of the CH2 domain of the antibody as well as aggregation onset temperatures were observed from DSC and DLS, respectively. However, no significant differences in secondary and tertiary structure were observed with Raman spectroscopy, or binding affinity as measured by ITC. Lysine-based ADC conjugation produces an innately heterogeneous population that can generate significant variability in the results of sensitive characterization techniques. Characterization of these ADCs indicated nominal differences in thermal stability but not in tertiary structure or binding affinity. Our results lead us to conclude that lysine-based ADCs synthesized following Protein A immobilization, common in small-scale conjugations, are highly similar to equivalent ADCs produced in larger scale, solution-based methods. Full article
(This article belongs to the Special Issue Antibody Drug Conjugates)
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Open AccessCommunication Structural Changes in Stx1 Engineering Monoclonal Antibody Improves Its Functionality as Diagnostic Tool for a Rapid Latex Agglutination Test
Antibodies 2018, 7(1), 9; https://doi.org/10.3390/antib7010009
Received: 6 December 2017 / Revised: 10 January 2018 / Accepted: 26 January 2018 / Published: 1 February 2018
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Abstract
Stx1 toxin is one of the AB5 toxins of Shiga toxin-producing Escherichia coli (STEC) responsible for foodborne intoxication during outbreaks. The single-chain variable fragment (scFv) is the most common recombinant antibody format; it consists of both variable chains connected by a peptide
[...] Read more.
Stx1 toxin is one of the AB5 toxins of Shiga toxin-producing Escherichia coli (STEC) responsible for foodborne intoxication during outbreaks. The single-chain variable fragment (scFv) is the most common recombinant antibody format; it consists of both variable chains connected by a peptide linker with conserved specificity and affinity for antigen. The drawbacks of scFv production in bacteria are the heterologous expression, conformation and stability of the molecule, which could change the affinity for the antigen. In this work, we obtained a stable and functional scFv-Stx1 in bacteria, starting from IgG produced by hybridoma cells. After structural modifications, i.e., change in protein orientation, vector and linker, its solubility for expression in bacteria was increased as well as the affinity for its antigen, demonstrated by a scFv dissociation constant (KD) of 2.26 × 10−7 M. Also, it was able to recognize purified Stx1 and cross-reacted with Stx2 toxin by ELISA (Enzyme-Linked Immunosorbent Assay), and detected 88% of Stx1-producing strains using a rapid latex agglutination test. Thus, the scFv fragment obtained in the present work is a bacteria-produced tool for use in a rapid diagnosis test, providing an alternative for STEC diagnosis. Full article
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Open AccessArticle A Polar Sulfamide Spacer Significantly Enhances the Manufacturability, Stability, and Therapeutic Index of Antibody–Drug Conjugates
Antibodies 2018, 7(1), 12; https://doi.org/10.3390/antib7010012
Received: 11 January 2018 / Revised: 8 February 2018 / Accepted: 17 February 2018 / Published: 20 February 2018
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Abstract
Despite tremendous efforts in the field of targeted cancer therapy with antibody–drug conjugates (ADCs), attrition rates have been high. Historically, the priority in ADC development has been the selection of target, antibody, and toxin, with little focus on the nature of the linker.
[...] Read more.
Despite tremendous efforts in the field of targeted cancer therapy with antibody–drug conjugates (ADCs), attrition rates have been high. Historically, the priority in ADC development has been the selection of target, antibody, and toxin, with little focus on the nature of the linker. We show here that a short and polar sulfamide spacer (HydraSpace™, Oss, The Netherlands) positively impacts ADC properties in various ways: (a) efficiency of conjugation; (b) stability; and (c) therapeutic index. Different ADC formats are explored in terms of drug-to-antibody ratios (DAR2, DAR4) and we describe the generation of a DAR4 ADC by site-specific attachment of a bivalent linker–payload construct to a single conjugation site in the antibody. A head-to-head comparison of HydraSpace™-containing DAR4 ADCs to marketed drugs, derived from the same antibody and toxic payload components, indicated a significant improvement in both the efficacy and safety of several vivo models, corroborated by in-depth pharmacokinetic analysis. Taken together, HydraSpace™ technology based on a polar sulfamide spacer provides significant improvement in manufacturability, stability, and ADC design, and is a powerful platform to enable next-generation ADCs with enhanced therapeutic index. Full article
(This article belongs to the Special Issue Antibody Drug Conjugates)
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Open AccessArticle Evaluation of Continuous Membrane Chromatography Concepts with an Enhanced Process Simulation Approach
Antibodies 2018, 7(1), 13; https://doi.org/10.3390/antib7010013
Received: 3 January 2018 / Revised: 20 February 2018 / Accepted: 27 February 2018 / Published: 2 March 2018
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Abstract
Modern biopharmaceutical products strive for small-scale, low-cost production. Continuous chromatography has shown to be a promising technology because it assures high-capacity utilization, purity and yield increases, and lower facility footprint. Membrane chromatography is a fully disposable low-cost alternative to bead-based chromatography with minor
[...] Read more.
Modern biopharmaceutical products strive for small-scale, low-cost production. Continuous chromatography has shown to be a promising technology because it assures high-capacity utilization, purity and yield increases, and lower facility footprint. Membrane chromatography is a fully disposable low-cost alternative to bead-based chromatography with minor drawbacks in terms of capacity. Hence, continuous membrane chromatography should have a high potential. The evaluation of continuous processes goes often along with process modeling. Only few experiments with small feed demand need to be conducted to estimate the model parameters. Afterwards, a variety of different process setups and working points can be analyzed in a very short time, making the approach very efficient. Since the available modeling approaches for membrane chromatography modules did not fit the used design, a new modeling approach is shown. This combines the general rate model with an advanced fluid dynamic distribution. Model parameter determination and model validation were done with industrial cell cultures containing Immunoglobulin G (IgG). The validated model was used to evaluate the feasibility of the integrated Counter Current Chromatography (iCCC) concept and the sequential chromatography concept for membrane adsorber modules, starting with a laboratory-type module used for sample preparation. A case study representing a fed-batch reactor with a capacity from 20 to 2000 L was performed. Compared to batch runs, a 71% higher capacity, 48.5% higher productivity, and 38% lower eluent consumption could be achieved. Full article
(This article belongs to the Special Issue Analytical Methodologies for Antibodies)
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Review

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Open AccessFeature PaperReview Myelin Antigens and Antimyelin Antibodies
Antibodies 2018, 7(1), 2; https://doi.org/10.3390/antib7010002
Received: 8 December 2017 / Revised: 20 December 2017 / Accepted: 22 December 2017 / Published: 2 January 2018
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Abstract
The purpose of this review is to provide an historical perspective on studies of serum derived antimyelin antibodies. Antimyelin antibodies can be defined by their action on myelinating organotypic nervous system tissue cultures and include demyelinating antibodies, which have destructive effects on myelin
[...] Read more.
The purpose of this review is to provide an historical perspective on studies of serum derived antimyelin antibodies. Antimyelin antibodies can be defined by their action on myelinating organotypic nervous system tissue cultures and include demyelinating antibodies, which have destructive effects on myelin when applied to already myelinated cultures, and myelination inhibiting antibodies, which prevent myelin formation when applied to cultures prior to myelination. Myelin antigens were evaluated in animal studies for their ability to induce experimental allergic encephalomyelitis, an inflammatory demyelinating disease, and correlated with the induction of antimyelin antibodies. As tissue culture demyelinating activity was also found in sera from some patients with multiple sclerosis, a human inflammatory demyelinating disease, studies were undertaken to characterize the nature of the demyelinating factors. Full article
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Open AccessReview Enzyme-Based Labeling Strategies for Antibody–Drug Conjugates and Antibody Mimetics
Antibodies 2018, 7(1), 4; https://doi.org/10.3390/antib7010004
Received: 1 November 2017 / Revised: 15 December 2017 / Accepted: 18 December 2017 / Published: 4 January 2018
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Abstract
Strategies for site-specific modification of proteins have increased in number, complexity, and specificity over the last years. Such modifications hold the promise to broaden the use of existing biopharmaceuticals or to tailor novel proteins for therapeutic or diagnostic applications. The recent quest for
[...] Read more.
Strategies for site-specific modification of proteins have increased in number, complexity, and specificity over the last years. Such modifications hold the promise to broaden the use of existing biopharmaceuticals or to tailor novel proteins for therapeutic or diagnostic applications. The recent quest for next-generation antibody–drug conjugates (ADCs) sparked research into techniques with site selectivity. While purely chemical approaches often impede control of dosage or locus of derivatization, naturally occurring enzymes and proteins bear the ability of co- or post-translational protein modifications at particular residues, thus enabling unique coupling reactions or protein fusions. This review provides a general overview and focuses on chemo-enzymatic methods including enzymes such as formylglycine-generating enzyme, sortase, and transglutaminase. Applications for the conjugation of antibodies and antibody mimetics are reported. Full article
(This article belongs to the Special Issue Therapeutic Antibodies)
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Open AccessReview Pharmacokinetic and Pharmacodynamic Considerations for the Use of Monoclonal Antibodies in the Treatment of Bacterial Infections
Antibodies 2018, 7(1), 5; https://doi.org/10.3390/antib7010005
Received: 8 December 2017 / Revised: 1 January 2018 / Accepted: 2 January 2018 / Published: 4 January 2018
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Abstract
Antibiotic-resistant bacterial pathogens are increasingly implicated in hospital- and community-acquired infections. Recent advances in monoclonal antibody (mAb) production and engineering have led to renewed interest in the development of antibody-based therapies for treatment of drug-resistant bacterial infections. Currently, there are three antibacterial mAb
[...] Read more.
Antibiotic-resistant bacterial pathogens are increasingly implicated in hospital- and community-acquired infections. Recent advances in monoclonal antibody (mAb) production and engineering have led to renewed interest in the development of antibody-based therapies for treatment of drug-resistant bacterial infections. Currently, there are three antibacterial mAb products approved by the Food and Drug Administration (FDA) and at least nine mAbs are in clinical trials. Antibacterial mAbs are typically developed to kill bacteria or to attenuate bacterial pathological activity through neutralization of bacterial toxins and virulence factors. Antibodies exhibit distinct pharmacological mechanisms from traditional antimicrobials and, hence, cross-resistance between small molecule antimicrobials and antibacterial mAbs is unlikely. Additionally, the long biological half-lives typically found for mAbs may allow convenient dosing and vaccine-like prophylaxis from infection. However, the high affinity of mAbs and the involvement of the host immune system in their pharmacological actions may lead to complex and nonlinear pharmacokinetics and pharmacodynamics. In this review, we summarize the pharmacokinetics and pharmacodynamics of the FDA-approved antibacterial mAbs and those are currently in clinical trials. Challenges in the development of antibacterial mAbs are also discussed. Full article
(This article belongs to the Special Issue Monoclonal Antibodies) Printed Edition available
Open AccessReview Therapeutic Antibody-Like Immunoconjugates against Tissue Factor with the Potential to Treat Angiogenesis-Dependent as Well as Macrophage-Associated Human Diseases
Antibodies 2018, 7(1), 8; https://doi.org/10.3390/antib7010008
Received: 10 October 2017 / Revised: 10 January 2018 / Accepted: 18 January 2018 / Published: 23 January 2018
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Abstract
Accumulating evidence suggests that tissue factor (TF) is selectively expressed in pathological angiogenesis-dependent as well as macrophage-associated human diseases. Pathological angiogenesis, the formation of neovasculature, is involved in many clinically significant human diseases, notably cancer, age-related macular degeneration (AMD), endometriosis and rheumatoid arthritis
[...] Read more.
Accumulating evidence suggests that tissue factor (TF) is selectively expressed in pathological angiogenesis-dependent as well as macrophage-associated human diseases. Pathological angiogenesis, the formation of neovasculature, is involved in many clinically significant human diseases, notably cancer, age-related macular degeneration (AMD), endometriosis and rheumatoid arthritis (RA). Macrophage is involved in the progression of a variety of human diseases, such as atherosclerosis and viral infections (human immunodeficiency virus, HIV and Ebola). It is well documented that TF is selectively expressed on angiogenic vascular endothelial cells (VECs) in these pathological angiogenesis-dependent human diseases and on disease-associated macrophages. Under physiology condition, TF is not expressed by quiescent VECs and monocytes but is solely restricted on some cells (such as pericytes) that are located outside of blood circulation and the inner layer of blood vessel walls. Here, we summarize TF expression on angiogenic VECs, macrophages and other diseased cell types in these human diseases. In cancer, for example, the cancer cells also overexpress TF in solid cancers and leukemia. Moreover, our group recently reported that TF is also expressed by cancer-initiating stem cells (CSCs) and can serve as a novel oncotarget for eradication of CSCs without drug resistance. Furthermore, we review and discuss two generations of TF-targeting therapeutic antibody-like immunoconjugates (ICON and L-ICON1) and antibody-drug conjugates that are currently being tested in preclinical and clinical studies for the treatment of some of these human diseases. If efficacy and safety are proven in current and future clinical trials, TF-targeting immunoconjugates may provide novel therapeutic approaches with potential to broadly impact the treatment regimen of these significant angiogenesis-dependent, as well as macrophage-associated, human diseases. Full article
(This article belongs to the Special Issue Therapeutic Antibodies)
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Open AccessFeature PaperReview Factors Affecting the Pharmacology of Antibody–Drug Conjugates
Antibodies 2018, 7(1), 10; https://doi.org/10.3390/antib7010010
Received: 14 December 2017 / Revised: 30 January 2018 / Accepted: 1 February 2018 / Published: 7 February 2018
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Abstract
Major advances in therapeutic proteins, including antibody–drug conjugates (ADCs), have created revolutionary drug delivery systems in cancer over the past decade. While these immunoconjugate agents provide several advantages compared to their small-molecule counterparts, their clinical use is still in its infancy. The considerations
[...] Read more.
Major advances in therapeutic proteins, including antibody–drug conjugates (ADCs), have created revolutionary drug delivery systems in cancer over the past decade. While these immunoconjugate agents provide several advantages compared to their small-molecule counterparts, their clinical use is still in its infancy. The considerations in their development and clinical use are complex, and consist of multiple components and variables that can affect the pharmacologic characteristics. It is critical to understand the mechanisms employed by ADCs in navigating biological barriers and how these factors affect their biodistribution, delivery to tumors, efficacy, and toxicity. Thus, future studies are warranted to better understand the complex pharmacology and interaction between ADC carriers and biological systems, such as the mononuclear phagocyte system (MPS) and tumor microenvironment. This review provides an overview of factors that affect the pharmacologic profiles of ADC therapies that are currently in clinical use and development. Full article
(This article belongs to the Special Issue Antibody Drug Conjugates)
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Open AccessReview Challenges in Optimising the Successful Construction of Antibody Drug Conjugates in Cancer Therapy
Antibodies 2018, 7(1), 11; https://doi.org/10.3390/antib7010011
Received: 13 December 2017 / Revised: 7 February 2018 / Accepted: 9 February 2018 / Published: 13 February 2018
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Abstract
Although considerable progress has been made in the field of cancer chemotherapy, there remains a significant unmet medical need, with a requirement to move away from traditional cytotoxics and explore novel, smarter chemotherapeutic approaches. One such example of the smart chemotherapy approach is
[...] Read more.
Although considerable progress has been made in the field of cancer chemotherapy, there remains a significant unmet medical need, with a requirement to move away from traditional cytotoxics and explore novel, smarter chemotherapeutic approaches. One such example of the smart chemotherapy approach is antibody-drug conjugates (ADCs), which consist of an antibody that binds selectively to a cancer antigen linked to a cytotoxic agent. When developing an ADC, it may be necessary to produce a variety of constructs to fully assess the optimal configuration for the molecule. By testing ADCs prepared using a range of cytotoxic agents, linkers, or different antibodies, it is possible to fully assess the optimal approach for this treatment modality before advancing to the clinic. Since the development and approval of first-generation ADCs, significant improvements in development technology have occurred. Here, we consider the advances made within the field of ADCs, focusing on the development of EDO-B278 and EDO-B776, both of which have demonstrated efficacy in preclinical testing. Although some limitations remain in this field of development, the potential reduction in toxicity offered by ADCs justifies the investment in research to find workable solutions that could ultimately provide patients with superior outcomes. Full article
(This article belongs to the Special Issue Antibody Drug Conjugates)
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Open AccessReview Infusion Reactions Associated with the Medical Application of Monoclonal Antibodies: The Role of Complement Activation and Possibility of Inhibition by Factor H
Antibodies 2018, 7(1), 14; https://doi.org/10.3390/antib7010014
Received: 24 December 2017 / Revised: 1 March 2018 / Accepted: 8 March 2018 / Published: 14 March 2018
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Abstract
Human application of monoclonal antibodies (mAbs), enzymes, as well as contrast media and many other particulate drugs and agents referred to as “nanomedicines”, can initiate pseudoallergic hypersensitivity reactions, also known as infusion reactions. These may in part be mediated by the activation of
[...] Read more.
Human application of monoclonal antibodies (mAbs), enzymes, as well as contrast media and many other particulate drugs and agents referred to as “nanomedicines”, can initiate pseudoallergic hypersensitivity reactions, also known as infusion reactions. These may in part be mediated by the activation of the complement system, a major humoral defense system of innate immunity. In this review, we provide a brief outline of complement activation-related pseudoallergy (CARPA) in general, and then focus on the reactions caused by mAb therapy. Because the alternative pathway of complement activation may amplify such adverse reactions, we highlight the potential use of complement factor H as an inhibitor of CARPA. Full article
(This article belongs to the Special Issue Monoclonal Antibodies) Printed Edition available
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