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ARS Medica Tomitana     Open Access   (Followers: 1)
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Journal Cover
Journal Prestige (SJR): 0.931
Citation Impact (citeScore): 3
Number of Followers: 2  

  This is an Open Access Journal Open Access journal
ISSN (Print) 2073-4468
Published by MDPI Homepage  [203 journals]
  • Antibodies, Vol. 7, Pages 15: Hydrophilic Auristatin Glycoside Payload
           Enables Improved Antibody-Drug Conjugate Efficacy and Biocompatibility

    • Authors: Tero Satomaa, Henna Pynnönen, Anja Vilkman, Titta Kotiranta, Virve Pitkänen, Annamari Heiskanen, Bram Herpers, Leo Price, Jari Helin, Juhani Saarinen
      First page: 15
      Abstract: Antibody-drug conjugates (ADCs) offer a combination of antibody therapy and specific delivery of potent small-molecule payloads to target cells. The properties of the ADC molecule are determined by the balance of its components. The efficacy of the payload component increases with higher drug-to-antibody ratio (DAR), while homogeneous DAR = 8 ADCs are easily prepared by conjugation to the four accessible antibody hinge cystines. However, use of hydrophobic payloads has permitted only DAR = 2–4, due to poor pharmacokinetics and aggregation problems. Here, we describe generation and characterization of homogeneous DAR = 8 ADCs carrying a novel auristatin β-D-glucuronide, MMAU. The glycoside payload contributed to overall hydrophilicity of the ADC reducing aggregation. Compared to standard DAR = 2–4 ADCs, cytotoxicity of the homogeneous DAR = 8 ADCs was improved to low-picomolar IC50 values against cancer cells in vitro. Bystander efficacy was restored after ADC internalization and subsequent cleavage of the glycoside, although unconjugated MMAU was relatively non-toxic to cells. DAR = 8 MMAU ADCs were effective against target antigen-expressing xenograft tumors. The ADCs were also studied in 3D in vitro patient-derived xenograft (PDX) assays where they outperformed clinically used ADC. In conclusion, increased hydrophilicity of the payload contributed to the ADC’s hydrophilicity, stability and safety to non-target cells, while significantly improving cytotoxicity and enabling bystander efficacy.
      Citation: Antibodies
      PubDate: 2018-03-22
      DOI: 10.3390/antib7020015
      Issue No: Vol. 7, No. 2 (2018)
  • Antibodies, Vol. 7, Pages 16: Small-Format Drug Conjugates: A Viable
           Alternative to ADCs for Solid Tumours'

    • Authors: Mahendra Deonarain, Gokhan Yahioglu, Ioanna Stamati, Anja Pomowski, James Clarke, Bryan Edwards, Soraya Diez-Posada, Ashleigh Stewart
      First page: 16
      Abstract: Antibody–Drug Conjugates (ADCs) have been through multiple cycles of technological innovation since the concept was first practically demonstrated ~40 years ago. Current technology is focusing on large, whole immunoglobulin formats (of which there are approaching 100 in clinical development), many with site-specifically conjugated payloads numbering 2 or 4. Despite the success of trastuzumab-emtansine in breast cancer, ADCs have generally failed to have an impact in solid tumours, leading many to explore alternative, smaller formats which have better penetrating properties as well as more rapid pharmacokinetics (PK). This review describes research and development progress over the last ~10 years obtained from the primary literature or conferences covering over a dozen different smaller format-drug conjugates from 80 kDa to around 1 kDa in total size. In general, these agents are potent in vitro, particularly more recent ones incorporating ultra-potent payloads such as auristatins or maytansinoids, but this potency profile changes when testing in vivo due to the more rapid clearance. Strategies to manipulate the PK properties, whilst retaining the more effective tumour penetrating properties could at last make small-format drug conjugates viable alternative therapeutics to the more established ADCs.
      Citation: Antibodies
      PubDate: 2018-03-31
      DOI: 10.3390/antib7020016
      Issue No: Vol. 7, No. 2 (2018)
  • Antibodies, Vol. 7, Pages 17: Special Issue: Monoclonal Antibodies

    • Authors: Christian Klein
      First page: 17
      Abstract: Monoclonal antibodies are utilized in clinical practice for the treatment of various diseases including cancer, autoimmunity, metabolic and infectious diseases [...]
      Citation: Antibodies
      PubDate: 2018-04-10
      DOI: 10.3390/antib7020017
      Issue No: Vol. 7, No. 2 (2018)
  • Antibodies, Vol. 7, Pages 2: Myelin Antigens and Antimyelin Antibodies

    • Authors: Fredrick Seil
      First page: 2
      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 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.
      Citation: Antibodies
      PubDate: 2018-01-02
      DOI: 10.3390/antib7010002
      Issue No: Vol. 7, No. 1 (2018)
  • Antibodies, Vol. 7, Pages 3: Tumor-Directed Blockade of CD47 with
           Bispecific Antibodies Induces Adaptive Antitumor Immunity

    • Authors: Elie Dheilly, Stefano Majocchi, Valéry Moine, Gérard Didelot, Lucile Broyer, Sébastien Calloud, Pauline Malinge, Laurence Chatel, Walter Ferlin, Marie Kosco-Vilbois, Nicolas Fischer, Krzysztof Masternak
      First page: 3
      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 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.
      Citation: Antibodies
      PubDate: 2018-01-03
      DOI: 10.3390/antib7010003
      Issue No: Vol. 7, No. 1 (2018)
  • Antibodies, Vol. 7, Pages 4: Enzyme-Based Labeling Strategies for
           Antibody–Drug Conjugates and Antibody Mimetics

    • Authors: Georg Falck, Kristian Müller
      First page: 4
      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 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.
      Citation: Antibodies
      PubDate: 2018-01-04
      DOI: 10.3390/antib7010004
      Issue No: Vol. 7, No. 1 (2018)
  • Antibodies, Vol. 7, Pages 5: Pharmacokinetic and Pharmacodynamic
           Considerations for the Use of Monoclonal Antibodies in the Treatment of
           Bacterial Infections

    • Authors: Shun Wang-Lin, Joseph Balthasar
      First page: 5
      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 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.
      Citation: Antibodies
      PubDate: 2018-01-04
      DOI: 10.3390/antib7010005
      Issue No: Vol. 7, No. 1 (2018)
  • Antibodies, Vol. 7, Pages 6: In-Depth Comparison of Lysine-Based
           Antibody-Drug Conjugates Prepared on Solid Support Versus in Solution

    • Authors: Keith Arlotta, Aditya Gandhi, Hsiao-Nung Chen, Christine Nervig, John Carpenter, Shawn Owen
      First page: 6
      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 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.
      Citation: Antibodies
      PubDate: 2018-01-07
      DOI: 10.3390/antib7010006
      Issue No: Vol. 7, No. 1 (2018)
  • Antibodies, Vol. 7, Pages 7: Acknowledgement to Reviewers of Antibodies in

    • Authors: Antibodies Editorial Office
      First page: 7
      Abstract: Peer review is an essential part in the publication process, ensuring that Antibodies maintains high quality standards for its published papers.[...]
      Citation: Antibodies
      PubDate: 2018-01-10
      DOI: 10.3390/antib7010007
      Issue No: Vol. 7, No. 1 (2018)
  • Antibodies, Vol. 7, Pages 8: Therapeutic Antibody-Like Immunoconjugates
           against Tissue Factor with the Potential to Treat Angiogenesis-Dependent
           as Well as Macrophage-Associated Human Diseases

    • Authors: Zhiwei Hu
      First page: 8
      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 (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.
      Citation: Antibodies
      PubDate: 2018-01-23
      DOI: 10.3390/antib7010008
      Issue No: Vol. 7, No. 1 (2018)
  • Antibodies, Vol. 7, Pages 9: Structural Changes in Stx1 Engineering
           Monoclonal Antibody Improves Its Functionality as Diagnostic Tool for a
           Rapid Latex Agglutination Test

    • Authors: Daniela Luz, Emerson Shiga, Gang Chen, Wagner Quintilio, Fernanda Andrade, Andrea Maranhão, Bruna Caetano, Thaís Mitsunari, Míriam Silva, Letícia Rocha, Ana Moro, Sachdev Sidhu, Roxane Piazza
      First page: 9
      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 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.
      Citation: Antibodies
      PubDate: 2018-02-01
      DOI: 10.3390/antib7010009
      Issue No: Vol. 7, No. 1 (2018)
  • Antibodies, Vol. 7, Pages 10: Factors Affecting the Pharmacology of
           Antibody–Drug Conjugates

    • Authors: Andrew Lucas, Lauren Price, Allison Schorzman, Mallory Storrie, Joseph Piscitelli, Juan Razo, William Zamboni
      First page: 10
      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 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.
      Citation: Antibodies
      PubDate: 2018-02-07
      DOI: 10.3390/antib7010010
      Issue No: Vol. 7, No. 1 (2018)
  • Antibodies, Vol. 7, Pages 11: Challenges in Optimising the Successful
           Construction of Antibody Drug Conjugates in Cancer Therapy

    • Authors: Thomas Mehrling, Daniel Soltis
      First page: 11
      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 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.
      Citation: Antibodies
      PubDate: 2018-02-13
      DOI: 10.3390/antib7010011
      Issue No: Vol. 7, No. 1 (2018)
  • Antibodies, Vol. 7, Pages 12: A Polar Sulfamide Spacer Significantly
           Enhances the Manufacturability, Stability, and Therapeutic Index of
           Antibody–Drug Conjugates

    • Authors: Jorge Verkade, Marloes Wijdeven, Remon van Geel, Brian Janssen, Sander van Berkel, Floris van Delft
      First page: 12
      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. We show here that a short and polar sulfamide spacer (HydraSpace™, AE Oss, the Netherland) 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.
      Citation: Antibodies
      PubDate: 2018-02-20
      DOI: 10.3390/antib7010012
      Issue No: Vol. 7, No. 1 (2018)
  • Antibodies, Vol. 7, Pages 13: Evaluation of Continuous Membrane
           Chromatography Concepts with an Enhanced Process Simulation Approach

    • Authors: Steffen Zobel-Roos, Dominik Stein, Jochen Strube
      First page: 13
      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 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.
      Citation: Antibodies
      PubDate: 2018-03-02
      DOI: 10.3390/antib7010013
      Issue No: Vol. 7, No. 1 (2018)
  • Antibodies, Vol. 7, Pages 14: Infusion Reactions Associated with the
           Medical Application of Monoclonal Antibodies: The Role of Complement
           Activation and Possibility of Inhibition by Factor H

    • Authors: Tamás Fülöp, Tamás Mészáros, Gergely Kozma, János Szebeni, Mihály Józsi
      First page: 14
      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 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.
      Citation: Antibodies
      PubDate: 2018-03-14
      DOI: 10.3390/antib7010014
      Issue No: Vol. 7, No. 1 (2018)
  • Antibodies, Vol. 7, Pages 1: Controlling the Glycosylation Profile in mAbs
           Using Time-Dependent Media Supplementation

    • Authors: Devesh Radhakrishnan, Anne Robinson, Babatunde Ogunnaike
      First page: 1
      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 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.
      Citation: Antibodies
      PubDate: 2017-12-21
      DOI: 10.3390/antib7010001
      Issue No: Vol. 7, No. 1 (2017)
  • Antibodies, Vol. 6, Pages 14: Epitope Sequences in Dengue Virus NS1
           Protein Identified by Monoclonal Antibodies

    • Authors: Leticia Rocha, Rubens Alves, Bruna Caetano, Lennon Pereira, Thais Mitsunari, Jaime Amorim, Juliana Polatto, Viviane Botosso, Neuza Gallina, Ricardo Palacios, Alexander Precioso, Celso Granato, Danielle Oliveira, Vanessa Silveira, Daniela Luz, Luís Ferreira, Roxane Piazza
      First page: 14
      Abstract: Dengue nonstructural protein 1 (NS1) is a multi-functional glycoprotein with essential functions both in viral replication and modulation of host innate immune responses. NS1 has been established as a good surrogate marker for infection. In the present study, we generated four anti-NS1 monoclonal antibodies against recombinant NS1 protein from dengue virus serotype 2 (DENV2), which were used to map three NS1 epitopes. The sequence 193AVHADMGYWIESALNDT209 was recognized by monoclonal antibodies 2H5 and 4H1BC, which also cross-reacted with Zika virus (ZIKV) protein. On the other hand, the sequence 25VHTWTEQYKFQPES38 was recognized by mAb 4F6 that did not cross react with ZIKV. Lastly, a previously unidentified DENV2 NS1-specific epitope, represented by the sequence 127ELHNQTFLIDGPETAEC143, is described in the present study after reaction with mAb 4H2, which also did not cross react with ZIKV. The selection and characterization of the epitope, specificity of anti-NS1 mAbs, may contribute to the development of diagnostic tools able to differentiate DENV and ZIKV infections.
      Citation: Antibodies
      PubDate: 2017-10-15
      DOI: 10.3390/antib6040014
      Issue No: Vol. 6, No. 4 (2017)
  • Antibodies, Vol. 6, Pages 15: Antibody Selection for Cancer Target
           Validation of FSH-Receptor in Immunohistochemical Settings

    • Authors: Nina Moeker, Solveig Peters, Robert Rauchenberger, Nicolae Ghinea, Christian Kunz
      First page: 15
      Abstract: Background: The follicle-stimulating hormone (FSH)-receptor (FSHR) has been reported to be an attractive target for antibody therapy in human cancer. However, divergent immunohistochemical (IHC) findings have been reported for FSHR expression in tumor tissues, which could be due to the specificity of the antibodies used. Methods: Three frequently used antibodies (sc-7798, sc-13935, and FSHR323) were validated for their suitability in an immunohistochemical study for FSHR expression in different tissues. As quality control, two potential therapeutic anti-hFSHR Ylanthia® antibodies (Y010913, Y010916) were used. The specificity criteria for selection of antibodies were binding to native hFSHR of different sources, and no binding to non-related proteins. The ability of antibodies to stain the paraffin-embedded Flp-In Chinese hamster ovary (CHO)/FSHR cells was tested after application of different epitope retrieval methods. Results: From the five tested anti-hFSHR antibodies, only Y010913, Y010916, and FSHR323 showed specific binding to native, cell-presented hFSHR. Since Ylanthia® antibodies were selected to specifically recognize native FSHR, as required for a potential therapeutic antibody candidate, FSHR323 was the only antibody to detect the receptor in IHC/histochemical settings on transfected cells, and at markedly lower, physiological concentrations (ex., in Sertoli cells of human testes). The pattern of FSH323 staining noticed for ovarian, prostatic, and renal adenocarcinomas indicated that FSHR was expressed mainly in the peripheral tumor blood vessels. Conclusion: Of all published IHC antibodies tested, only antibody FSHR323 proved suitable for target validation of hFSHR in an IHC setting for cancer. Our studies could not confirm the previously reported FSHR overexpression in ovarian and prostate cancer cells. Instead, specific overexpression in peripheral tumor blood vessels could be confirmed after thorough validation of the antibodies used.
      Citation: Antibodies
      PubDate: 2017-10-18
      DOI: 10.3390/antib6040015
      Issue No: Vol. 6, No. 4 (2017)
  • Antibodies, Vol. 6, Pages 16: Antibodies and Derivatives Targeting DR4 and
           DR5 for Cancer Therapy

    • Authors: Agathe Dubuisson, Olivier Micheau
      First page: 16
      Abstract: Developing therapeutics that induce apoptosis in cancer cells has become an increasingly attractive approach for the past 30 years. The discovery of tumor necrosis factor (TNF) superfamily members and more specifically TNF-related apoptosis-inducing ligand (TRAIL), the only cytokine of the family capable of eradicating selectively cancer cells, led to the development of numerous TRAIL derivatives targeting death receptor 4 (DR4) and death receptor 5 (DR5) for cancer therapy. With a few exceptions, preliminary attempts to use recombinant TRAIL, agonistic antibodies, or derivatives to target TRAIL agonist receptors in the clinic have been fairly disappointing. Nonetheless, a tremendous effort, worldwide, is being put into the development of novel strategic options to target TRAIL receptors. Antibodies and derivatives allow for the design of novel and efficient agonists. We summarize and discuss here the advantages and drawbacks of the soar of TRAIL therapeutics, from the first developments to the next generation of agonistic products, with a particular insight on new concepts.
      Citation: Antibodies
      PubDate: 2017-10-25
      DOI: 10.3390/antib6040016
      Issue No: Vol. 6, No. 4 (2017)
  • Antibodies, Vol. 6, Pages 17: Therapeutic and Diagnostic Antibodies to
           CD146: Thirty Years of Research on Its Potential for Detection and
           Treatment of Tumors

    • Authors: Jimmy Stalin, Marie Nollet, Françoise Dignat-George, Nathalie Bardin, Marcel Blot-Chabaud
      First page: 17
      Abstract: CD146 (MCAM, MUC18, S-Endo1) is a transmembrane glycoprotein belonging to both CAM and mucin families. It exists as different splice variants and is cleaved from the membrane by metalloproteases to generate a soluble form. CD146 is expressed by numerous cancer cells as well as being one of the numerous proteins expressed by the vascular endothelium. It has also been identified on smooth muscle cells, pericytes, and some immune cells. This protein was initially described as an actor involved in tumor growth and metastatic dissemination processes. Some recent works highlighted the role of CD146 in angiogenesis. Interestingly, this knowledge allowed the development of therapeutic and diagnostic tools specifically targeting the different CD146 variants. The first anti-CD146 antibody designed to study the function of this molecule, MUC18, was described by the Pr. J.P. Jonhson in 1987. In this review, we will discuss the 30 following years of research focused on the detection, study, and blocking of this protein in physiological and pathological processes.
      Citation: Antibodies
      PubDate: 2017-11-05
      DOI: 10.3390/antib6040017
      Issue No: Vol. 6, No. 4 (2017)
  • Antibodies, Vol. 6, Pages 18: Monoclonal Antibody: A New Treatment
           Strategy against Multiple Myeloma

    • Authors: Shih-Feng Cho, Liang Lin, Lijie Xing, Tengteng Yu, Kenneth Wen, Kenneth C. Anderson, Yu-Tzu Tai
      First page: 18
      Abstract: 2015 was a groundbreaking year for the multiple myeloma community partly due to the breakthrough approval of the first two monoclonal antibodies in the treatment for patients with relapsed and refractory disease. Despite early disappointments, monoclonal antibodies targeting CD38 (daratumumab) and signaling lymphocytic activation molecule F7 (SLAMF7) (elotuzumab) have become available for patients with multiple myeloma in the same year. Specifically, phase 3 clinical trials of combination therapies incorporating daratumumab or elotuzumab indicate both efficacy and a very favorable toxicity profile. These therapeutic monoclonal antibodies for multiple myeloma can kill target cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent phagocytosis, as well as by direct blockade of signaling cascades. In addition, their immunomodulatory effects may simultaneously inhibit the immunosuppressive bone marrow microenvironment and restore the key function of immune effector cells. In this review, we focus on monoclonal antibodies that have shown clinical efficacy or promising preclinical anti-multiple myeloma activities that warrant further clinical development. We summarize mechanisms that account for the in vitro and in vivo anti-myeloma effects of these monoclonal antibodies, as well as relevant preclinical and clinical results. Monoclonal antibody-based immunotherapies have already and will continue to transform the treatment landscape in multiple myeloma.
      Citation: Antibodies
      PubDate: 2017-11-14
      DOI: 10.3390/antib6040018
      Issue No: Vol. 6, No. 4 (2017)
  • Antibodies, Vol. 6, Pages 19: Antagonist Anti-CD28 Therapeutics for the
           Treatment of Autoimmune Disorders

    • Authors: Bernard Vanhove, Nicolas Poirier, Fadi Fakhouri, Laetitia Laurent, Bert ’t Hart, Pedro Papotto, Luiz Rizzo, Masaaki Zaitsu, Fadi Issa, Kathryn Wood, Jean-Paul Soulillou, Gilles Blancho
      First page: 19
      Abstract: The effector functions of T lymphocytes are responsible for most autoimmune disorders and act by directly damaging tissues or by indirectly promoting inflammation and antibody responses. Co-stimulatory and co-inhibitory T cell receptor molecules are the primary pharmacological targets that enable interference with immune-mediated diseases. Among these, selective CD28 antagonists have drawn special interest, since they tip the co-stimulation/co-inhibition balance towards efficiently inhibiting effector T cells while promoting suppression by pre-existing regulatory T-cells. After having demonstrated outstanding therapeutic efficacy in multiple models of autoimmunity, inflammation and transplantation, and safety in phase-I studies in humans, selective CD28 antagonists are currently in early clinical development for the treatment of systemic lupus erythematous and rheumatoid arthritis. Here, we review the available proof of concept studies for CD28 antagonists in autoimmunity, with a special focus on the mechanisms of action.
      Citation: Antibodies
      PubDate: 2017-11-21
      DOI: 10.3390/antib6040019
      Issue No: Vol. 6, No. 4 (2017)
  • Antibodies, Vol. 6, Pages 20: Pyrrolobenzodiazepine Antibody-Drug
           Conjugates Designed for Stable Thiol Conjugation

    • Authors: R. Christie, Arnaud Tiberghien, Qun Du, Binyam Bezabeh, Ryan Fleming, Amanda Shannon, Shenlan Mao, Shannon Breen, Jing Zhang, Haihong Zhong, Jay Harper, Herren Wu, Philip Howard, Changshou Gao
      First page: 20
      Abstract: Thiosuccinimide-linked antibody-drug conjugates (ADCs) are susceptible to drug loss over time due to a retro-Michael reaction, which can be prevented by selecting stable conjugation positions or hydrolysis of the thiosuccinimide. Here, we investigate pyrrolobenzodiazepine (PBD) ADC drug-linkers equipped with N-phenyl maleimide functionality for stable thiol conjugation via thiosuccinimide hydrolysis. Two PBD drug-linker formats (enzyme-cleavable and non-cleavable) were evaluated following site-specific conjugation to an engineered cysteine incorporated at position T289, which is known to be unstable for N-alkyl maleimide conjugates. N-phenyl maleimide PBDs conjugated to antibodies with similar efficiencies as N-alkyl maleimide PBDs and enhanced thiosuccinimide hydrolysis for N-phenyl maleimide PBDs was confirmed by mass spectrometry, capillary isoelectric focusing, and a SYPRO Orange dye binding assay. All of the PBD ADCs were highly potent in vitro regardless of maleimide- or linker-type, exhibiting low pM EC50 values. Thiol conjugation to N-phenyl maleimide PBD minimized the retro-Michael reaction in both rat and mouse serum. However, cleavage of the valine-alanine dipeptide in mouse serum for ADCs containing cleavable drug-linker led to drug loss regardless of maleimide type, which impacted ADC potency in tumor growth inhibition studies that were conducted in mouse models. Therapeutic improvement in mouse tumor models was realized for ADCs prepared with non-cleavable PBD drug-linkers that were conjugated through N-phenyl maleimide, where a stronger tumor growth inhibition (TGI) response was achieved when compared to the analogous N-alkyl maleimide drug-linker ADC. Altogether, our findings highlight the stability and efficacy benefits of N-phenyl maleimide functionality for ADCs that are produced with thiol-maleimide conjugation chemistry.
      Citation: Antibodies
      PubDate: 2017-11-28
      DOI: 10.3390/antib6040020
      Issue No: Vol. 6, No. 4 (2017)
  • Antibodies, Vol. 6, Pages 21: Integration of Aqueous Two-Phase Extraction
           as Cell Harvest and Capture Operation in the Manufacturing Process of
           Monoclonal Antibodies

    • Authors: Axel Schmidt, Michael Richter, Frederik Rudolph, Jochen Strube
      First page: 21
      Abstract: Substantial improvements have been made to cell culturing processes (e.g., higher product titer) in recent years by raising cell densities and optimizing cultivation time. However, this has been accompanied by an increase in product-related impurities and therefore greater challenges in subsequent clarification and capture operations. Considering the paradigm shift towards the design of continuously operating dedicated plants at smaller scales—with or without disposable technology—for treating smaller patient populations due to new indications or personalized medicine approaches, the rising need for new, innovative strategies for both clarification and capture technology becomes evident. Aqueous two-phase extraction (ATPE) is now considered to be a feasible unit operation, e.g., for the capture of monoclonal antibodies or recombinant proteins. However, most of the published work so far investigates the applicability of ATPE in antibody-manufacturing processes at the lab-scale and for the most part, only during the capture step. This work shows the integration of ATPE as a combined harvest and capture step into a downstream process. Additionally, a model is applied that allows early prediction of settler dimensions with high prediction accuracy. Finally, a reliable process development concept, which guides through the necessary steps, starting from the definition of the separation task to the final stages of integration and scale-up, is presented.
      Citation: Antibodies
      PubDate: 2017-12-01
      DOI: 10.3390/antib6040021
      Issue No: Vol. 6, No. 4 (2017)
  • Antibodies, Vol. 6, Pages 22: Generation and Performance of R132H Mutant
           IDH1 Rabbit Monoclonal Antibody

    • Authors: Juliet Rashidian, Raul Copaciu, Qin Su, Brett Merritt, Claire Johnson, Aril Yahyabeik, Ella French, Kelsea Cummings
      First page: 22
      Abstract: Isocitrate dehydrogenase 1 (IDH1) gene mutations have been observed in a majority of diffuse astrocytomas, oligodendrogliomas, and secondary glioblastomas, and the mutant IDH1 R132H is detectable in most of these lesions. By specifically targeting the R132H mutation through B-cell cloning, a novel rabbit monoclonal antibody, MRQ-67, was produced that can recognize mutant IDH1 R132H and does not react with the wild type protein as demonstrated by Enzyme-linked immunosorbent assay (ELISA) and Western blotting. Through immunohistochemistry, the antibody is able to highlight neoplastic cells in glioma tissue specimens, and can be used as a tool in glioma subtyping. Immunohistochemistry (IHC) detection of IDH1 mutant protein may also be used to visualize single infiltrating tumor cells in surrounding brain tissue with an otherwise normal appearance.
      Citation: Antibodies
      PubDate: 2017-12-01
      DOI: 10.3390/antib6040022
      Issue No: Vol. 6, No. 4 (2017)
  • Antibodies, Vol. 6, Pages 23: Modulation of BCR Signaling by the Induced
           Dimerization of Receptor-Associated SYK

    • Authors: Mark Westbroek, Robert Geahlen
      First page: 23
      Abstract: Clustering of the B cell antigen receptor (BCR) by polyvalent antigens is transmitted through the SYK tyrosine kinase to the activation of multiple intracellular pathways that determine the physiological consequences of receptor engagement. To explore factors that modulate the quantity and quality of signals sent by the crosslinked BCR, we developed a novel chemical mediator of dimerization to induce clustering of receptor-associated SYK. To accomplish this, we fused SYK with E. coli dihydrofolate reductase (eDHFR), which binds the small molecule trimethoprim (TMP) with high affinity and selectivity and synthesized a dimer of TMP with a flexible linker. The TMP dimer is able to induce the aggregation of eDHFR-linked SYK in live cells. The induced dimerization of SYK bound to the BCR differentially regulates the activation of downstream transcription factors, promoting the activation of Nuclear Factor of Activated T cells (NFAT) without affecting the activation of NFκB. The dimerization of SYK enhances the duration but not the amplitude of calcium mobilization by enhancing the extent and duration of its interaction with the crosslinked BCR at the plasma membrane.
      Citation: Antibodies
      PubDate: 2017-12-07
      DOI: 10.3390/antib6040023
      Issue No: Vol. 6, No. 4 (2017)
  • Antibodies, Vol. 6, Pages 24: Process Analytical Approach towards Quality
           Controlled Process Automation for the Downstream of Protein Mixtures by
           Inline Concentration Measurements Based on Ultraviolet/Visible Light
           (UV/VIS) Spectral Analysis

    • Authors: Steffen Zobel-Roos, Mourad Mouellef, Christian Siemers, Jochen Strube
      First page: 24
      Abstract: Downstream of pharmaceutical proteins, such as monoclonal antibodies, is mainly done by chromatography, where concentration determination of coeluting components presents a major problem. Inline concentration measurements (ICM) by Ultraviolet/Visible light (UV/VIS)-spectral data analysis provide a label-free and noninvasive approach to significantly speed up the analysis and process time. Here, two different approaches are presented. For a test mixture of three proteins, a fast and easily calibrated method based on the non-negative least-squares algorithm is shown, which reduces the calibration effort compared to a partial least-squares approach. The accuracy of ICM for analytical separations of three proteins on an ion exchange column is over 99%, compared to less than 85% for classical peak area evaluation. The power of the partial least squares algorithm (PLS) is shown by measuring the concentrations of Immunoglobulin G (IgG) monomer and dimer under a worst-case scenario of completely overlapping peaks. Here, the faster SIMPLS algorithm is used in comparison to the nonlinear iterative partial least squares (NIPALS) algorithm. Both approaches provide concentrations as well as purities in real-time, enabling live-pooling decisions based on product quality. This is one important step towards advanced process automation of chromatographic processes. Analysis time is less than 100 ms and only one program is used for all the necessary communications and calculations.
      Citation: Antibodies
      PubDate: 2017-12-12
      DOI: 10.3390/antib6040024
      Issue No: Vol. 6, No. 4 (2017)
  • Antibodies, Vol. 6, Pages 25: Characterization of Monoclonal
           Antibody–Protein Antigen Complexes Using Small-Angle Scattering and
           Molecular Modeling

    • Authors: Maria Castellanos, James Snyder, Melody Lee, Srinivas Chakravarthy, Nicholas Clark, Arnold McAuley, Joseph Curtis
      First page: 25
      Abstract: The determination of monoclonal antibody interactions with protein antigens in solution can lead to important insights guiding physical characterization and molecular engineering of therapeutic targets. We used small-angle scattering (SAS) combined with size-exclusion multi-angle light scattering high-performance liquid chromatography to obtain monodisperse samples with defined stoichiometry to study an anti-streptavidin monoclonal antibody interacting with tetrameric streptavidin. Ensembles of structures with both monodentate and bidentate antibody–antigen complexes were generated using molecular docking protocols and molecular simulations. By comparing theoretical SAS profiles to the experimental data it was determined that the primary component(s) were compact monodentate and/or bidentate complexes. SAS profiles of extended monodentate complexes were not consistent with the experimental data. These results highlight the capability for determining the shape of monoclonal antibody–antigen complexes in solution using SAS data and physics-based molecular modeling.
      Citation: Antibodies
      PubDate: 2017-12-15
      DOI: 10.3390/antib6040025
      Issue No: Vol. 6, No. 4 (2017)
  • Antibodies, Vol. 6, Pages 9: Potential Roles of Antiphospholipid
           Antibodies in Generating Platelet-C4d in Systemic Lupus Erythematosus

    • Authors: Chau-Ching Liu, Travis Schofield, Amy Tang, Susan Manzi, Joseph M. Ahearn
      First page: 9
      Abstract: Premature, accelerated onset of atherothrombotic disease is prevalent in patients with systemic lupus erythematosus (SLE). Most, if not all, atherothrombotic diseases are likely to involve platelets and complement. Previously, we discovered that platelets bearing complement activation product C4d (P-C4d) are present in SLE patients, and are significantly associated with antiphospholipid (aPL) antibody positivity and stroke in SLE patients. The goal of the present study was to further elucidate the role of aPL and other platelet-reactive autoantibodies in the generation of P-C4d. To determine the association between P-C4d and aPL antibodies, the serum levels of aPL antibodies and P-C4d of 180 SLE patients were measured by enzyme-linked immunoassays and flow cytometry, respectively. To investigate the role of aPL antibodies, and possibly other autoantibodies as well, in mediating the generation of P-C4d, in vitro 2-step P-C4d induction experiments were performed. The results showed that the presence and levels of aPL antibodies in the serum were specifically elevated in SLE patients with positive P-C4d. The plasma and immunoglobulins purified from SLE patients who were positive for P-C4d and aPL were capable of inducing C4d deposition on normal platelets in vitro. The capacity of SLE plasma in inducing P-C4d appeared to correlate proportionately to the serum aPL levels. Collectively, the results demonstrate that both aPL and other platelet-reactive autoantibodies may participate in mediating the generation of P-C4d in SLE patients.
      PubDate: 2017-07-02
      DOI: 10.3390/antib6030009
      Issue No: Vol. 6, No. 3 (2017)
  • Antibodies, Vol. 6, Pages 10: Strategies for Selecting Membrane
           Protein-Specific Antibodies using Phage Display with Cell-Based Panning

    • Authors: Mohamed Alfaleh, Martina Jones, Christopher Howard, Stephen Mahler
      First page: 10
      Abstract: Membrane proteins are attractive targets for monoclonal antibody (mAb) discovery and development. Although several approved mAbs against membrane proteins have been isolated from phage antibody libraries, the process is challenging, as it requires the presentation of a correctly folded protein to screen the antibody library. Cell-based panning could represent the optimal method for antibody discovery against membrane proteins, since it allows for presentation in their natural conformation along with the appropriate post-translational modifications. Nevertheless, screening antibodies against a desired antigen, within a selected cell line, may be difficult due to the abundance of irrelevant organic molecules, which can potentially obscure the antigen of interest. This review will provide a comprehensive overview of the different cell-based phage panning strategies, with an emphasis placed on the optimisation of four critical panning conditions: cell surface antigen presentation, non-specific binding events, incubation time, and temperature and recovery of phage binders.
      Citation: Antibodies
      PubDate: 2017-08-05
      DOI: 10.3390/antib6030010
      Issue No: Vol. 6, No. 3 (2017)
  • Antibodies, Vol. 6, Pages 11: Monoclonal Antibodies against Plasmodium
           falciparum Circumsporozoite Protein

    • Authors: Min Zhang, Rajakumar Mandraju, Urvashi Rai, Takayuki Shiratsuchi, Moriya Tsuji
      First page: 11
      Abstract: Malaria is a mosquito-borne infectious disease caused by the parasite Plasmodium spp. Malaria continues to have a devastating impact on human health. Sporozoites are the infective forms of the parasite inside mosquito salivary glands. Circumsporozoite protein (CSP) is a major and immunodominant protective antigen on the surface of Plasmodium sporozoites. Here, we report a generation of specific monoclonal antibodies that recognize the central repeat and C-terminal regions of P. falciparum CSP. The monoclonal antibodies 3C1, 3C2, and 3D3—specific for the central repeat region—have higher titers and protective efficacies against challenge with sporozoites compared with 2A10, a gold standard monoclonal antibody that was generated in early 1980s.
      Citation: Antibodies
      PubDate: 2017-08-23
      DOI: 10.3390/antib6030011
      Issue No: Vol. 6, No. 3 (2017)
  • Antibodies, Vol. 6, Pages 12: Functional, Biophysical, and Structural
           Characterization of Human IgG1 and IgG4 Fc Variants with Ablated Immune

    • Authors: Susan Tam, Stephen McCarthy, Anthony Armstrong, Sandeep Somani, Sheng-Jiun Wu, Xuesong Liu, Alexis Gervais, Robin Ernst, Dorina Saro, Rose Decker, Jinquan Luo, Gary Gilliland, Mark Chiu, Bernard Scallon
      First page: 12
      Abstract: Engineering of fragment crystallizable (Fc) domains of therapeutic immunoglobulin (IgG) antibodies to eliminate their immune effector functions while retaining other Fc characteristics has numerous applications, including blocking antigens on Fc gamma (Fcγ) receptor-expressing immune cells. We previously reported on a human IgG2 variant termed IgG2σ with barely detectable activity in antibody-dependent cellular cytotoxicity, phagocytosis, complement activity, and Fcγ receptor binding assays. Here, we extend that work to IgG1 and IgG4 antibodies, alternative subtypes which may offer advantages over IgG2 antibodies. In several in vitro and in vivo assays, the IgG1σ and IgG4σ variants showed equal or even lower Fc-related activities than the corresponding IgG2σ variant. In particular, IgG1σ and IgG4σ variants demonstrate complete lack of effector function as measured by antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, and in vivo T-cell activation. The IgG1σ and IgG4σ variants showed acceptable solubility and stability, and typical human IgG1 pharmacokinetic profiles in human FcRn-transgenic mice and cynomolgus monkeys. In silico T-cell epitope analyses predict a lack of immunogenicity in humans. Finally, crystal structures and simulations of the IgG1σ and IgG4σ Fc domains can explain the lack of Fc-mediated immune functions. These variants show promise for use in those therapeutic antibodies and Fc fusions for which the Fc domain should be immunologically “silent”.
      Citation: Antibodies
      PubDate: 2017-09-01
      DOI: 10.3390/antib6030012
      Issue No: Vol. 6, No. 3 (2017)
  • Antibodies, Vol. 6, Pages 13: Host Cell Proteins in Biologics
           Manufacturing: The Good, the Bad, and the Ugly

    • Authors: Martin Kornecki, Fabian Mestmäcker, Steffen Zobel-Roos, Laura Heikaus de Figueiredo, Hartmut Schlüter, Jochen Strube
      First page: 13
      Abstract: Significant progress in the manufacturing of biopharmaceuticals has been made by increasing the overall titers in the USP (upstream processing) titers without raising the cost of the USP. In addition, the development of platform processes led to a higher process robustness. Despite or even due to those achievements, novel challenges are in sight. The higher upstream titers created more complex impurity profiles, both in mass and composition, demanding higher separation capacities and selectivity in downstream processing (DSP). This creates a major shift of costs from USP to DSP. In order to solve this issue, USP and DSP integration approaches can be developed and used for overall process optimization. This study focuses on the characterization and classification of host cell proteins (HCPs) in each unit operation of the DSP (i.e., aqueous two-phase extraction, integrated countercurrent chromatography). The results create a data-driven feedback to the USP, which will serve for media and process optimizations in order to reduce, or even eliminate nascent critical HCPs. This will improve separation efficiency and may lead to a quantitative process understanding. Different HCP species were classified by stringent criteria with regard to DSP separation parameters into “The Good, the Bad, and the Ugly” in terms of pI and MW using 2D-PAGE analysis depending on their positions on the gels. Those spots were identified using LC-MS/MS analysis. HCPs, which are especially difficult to remove and persistent throughout the DSP (i.e., “Bad” or “Ugly”), have to be evaluated by their ability to be separated. In this approach, HCPs, considered “Ugly,” represent proteins with a MW larger than 15 kDa and a pI between 7.30 and 9.30. “Bad” HCPs can likewise be classified using MW (>15 kDa) and pI (4.75–7.30 and 9.30–10.00). HCPs with a MW smaller than 15 kDa and a pI lower than 4.75 and higher than 10.00 are classified as “Good” since their physicochemical properties differ significantly from the product. In order to evaluate this classification scheme, it is of utmost importance to use orthogonal analytical methods such as IEX, HIC, and SEC.
      Citation: Antibodies
      PubDate: 2017-09-16
      DOI: 10.3390/antib6030013
      Issue No: Vol. 6, No. 3 (2017)
  • Antibodies, Vol. 6, Pages 6: Collagen Autoantibodies and Their
           Relationship to CCP Antibodies and Rheumatoid Factor in the Progression of
           Early Rheumatoid Arthritis

    • Authors: Senga Whittingham, Alex Stockman, Merrill Rowley
      First page: 6
      Abstract: Serum autoantibodies to cyclic citrullinated peptides (anti-CCP) and rheumatoid factor (RF) are important markers for diagnosis and prognosis of rheumatoid arthritis (RA), but their autoantigens are not cartilage-specific. Autoantibodies to joint-specific type II collagen (CII) also occur in RA, and monoclonal antibodies of similar specificity induce collagen antibody-induced arthritis in animals, but their role in RA is uncertain. We utilized an enzyme-linked immunosorbent assay (ELISA) with the CB10 peptide of CII to compare the frequency of autoantibodies with those of anti-CCP and RF in stored sera from a prospective study of 82 patients with early RA to examine the outcome, defined as remission (n = 23), persisting non-erosive arthritis (n = 27), or erosions (n = 32). Initial frequencies of anti-CB10, anti-CCP and RF were 76%, 54%, and 57% in RA, and 4%, 0%, and 9% in 136 controls. The frequency of anti-CB10 was unrelated to outcome, but anti-CCP and RF increased with increasing severity, and the number of autoantibodies mirrored the severity. We suggest RA is an immune complex-mediated arthritis in which the three antibodies interact, with anti-CII inducing localized cartilage damage and inflammation resulting in citrullination of joint proteins, neoepitope formation, and a strong anti-CCP response in genetically-susceptible subjects, all amplified and modified by RF.
      PubDate: 2017-04-05
      DOI: 10.3390/antib6020006
      Issue No: Vol. 6, No. 2 (2017)
  • Antibodies, Vol. 6, Pages 7: Asymmetric Fc Engineering for Bispecific
           Antibodies with Reduced Effector Function

    • Authors: Eric Escobar-Cabrera, Paula Lario, Jason Baardsnes, Joseph Schrag, Yves Durocher, Surjit Dixit
      First page: 7
      Abstract: Asymmetric bispecific antibodies are a rapidly expanding therapeutic antibody class, designed to recognize two different target epitopes concurrently to achieve novel functions not available with normal antibodies. Many therapeutic designs require antibodies with reduced or silenced effector function. Although many solutions have been described in the literature to knockout effector function, to date all of them have involved the use of a specific antibody subtype (e.g., IgG2 or IgG4), or symmetric mutations in the lower hinge or CH2 domain of traditional homodimeric monospecific antibodies. In the context of a heterodimeric Fc, we describe novel asymmetric Fc mutations with reduced or silenced effector function in this article. These heteromultimeric designs contain asymmetric charged mutations in the lower hinge and the CH2 domain of the Fc. Surface plasmon resonance showed that the designed mutations display much reduced binding to all of the Fc gamma receptors and C1q. Ex vivo ADCC and CDC assays showed a consistent reduction in activity. Differential scanning calorimetry showed increased thermal stability for some of the designs. Finally, the asymmetric nature of the introduced charged mutations allowed for separation of homodimeric impurities by ion exchange chromatography, providing, as an added benefit, a purification strategy for the production of bispecific antibodies with reduced or silenced effector function.
      PubDate: 2017-05-16
      DOI: 10.3390/antib6020007
      Issue No: Vol. 6, No. 2 (2017)
  • Antibodies, Vol. 6, Pages 8: Dimerized Domain V of Beta2-Glycoprotein I Is
           Sufficient to Upregulate Procoagulant Activity in PMA-Treated U937
           Monocytes and Require Intact Residues in Two Phospholipid-Binding Loops

    • Authors: Alexey Kolyada, David Barrios, Natalia Beglova
      First page: 8
      Abstract: Upregulation of the procoagulant activity of monocytes by antibodies to beta2-glycoprotein I (β2GPI) is one of the mechanisms contributing to thrombosis in antiphospholipid syndrome. Current knowledge about receptors responsible for the upregulation of procoagulant activity by β2GPI/anti-β2GPI complexes and their binding sites on β2GPI is far from complete. We quantified the procoagulant activity expressed by phorbol 12-myristate 13-acetate (PMA)-differentiated U937 cells by measuring clotting kinetics in human plasma exposed to stimulated cells. Cells stimulated with anti-β2GPI were compared to cells treated with dimerized domain V of β2GPI (β2GPI-DV) or point mutants of β2GPI-DV. We demonstrated that dimerized β2GPI-DV is sufficient to induce procoagulant activity in monocytes. Using site-directed mutagenesis, we determined that the phospholipid-binding interface on β2GPI is larger than previously thought and includes Lys308 in β2GPI-DV. Intact residues in two phospholipid-binding loops of β2GPI-DV were important for the potentiation of procoagulant activity. We did not detect a correlation between the ability of β2GPI-DV variants to bind ApoER2 and potentiation of the procoagulant activity of cells. The region on β2GPI inducing procoagulant activity in monocytes can now be narrowed down to β2GPI-DV. The ability of β2GPI-DV dimers to come close to cell membrane and attach to it is important for the stimulation of procoagulant activity.
      PubDate: 2017-06-02
      DOI: 10.3390/antib6020008
      Issue No: Vol. 6, No. 2 (2017)
  • Antibodies, Vol. 6, Pages 1: Pathogenic and Protective Autoantibodies in
           Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED)

    • Authors: Sakeen Kashem, Bryce Binstadt
      First page: 1
      Abstract: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare disorder caused by mutations in the autoimmune regulator (AIRE) gene, leading to defects in T cell selection. The disease manifestations include both autoimmune tissue destruction and immunodeficiency, with specific susceptibility to chronic mucocutaneous candidiasis. Studies have demonstrated a wide repertoire of high affinity tissue- and cytokine-specific antibodies in patients with APECED. Here, we review the antigenic targets and function of these disease-causing and disease-ameliorating antibodies.
      PubDate: 2017-01-17
      DOI: 10.3390/antib6010001
      Issue No: Vol. 6, No. 1 (2017)
  • Antibodies, Vol. 6, Pages 2: Acknowledgement to Reviewers of Antibodies in

    • Authors: Antibodies Editorial Office
      First page: 2
      Abstract: The editors of Antibodies would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016.[...]
      PubDate: 2017-01-18
      DOI: 10.3390/antib6010002
      Issue No: Vol. 6, No. 1 (2017)
  • Antibodies, Vol. 6, Pages 3: Pairing Alpaca and Llama-Derived Single
           Domain Antibodies to Enhance Immunoassays for Ricin

    • Authors: Kendrick Turner, Sabrina Hardy, Jinny Liu, Dan Zabetakis, P. Lee, Ellen Goldman, George Anderson
      First page: 3
      Abstract: Previously, our group isolated and evaluated anti-ricin single domain antibodies (sdAbs) derived from llamas, engineered them to further increase their thermal stability, and utilized them for the development of sensitive immunoassays. In work focused on the development of therapeutics, Vance et al. 2013 described anti-ricin sdAbs derived from alpacas. Herein, we evaluated the utility of selected alpaca-derived anti-ricin sdAbs for detection applications, and engineered an alpaca-derived sdAb to increase its melting temperature, providing a highly thermal stable reagent for use in ricin detection. Four of the alpaca-derived anti-ricin A-chain sdAbs were produced and characterized. All four bound to epitopes that overlapped with our previously described llama sdAbs. One alpaca sdAb, F6, was found to possess both a high melting temperature (73 °C) and to work optimally with a thermally stable llama anti-ricin sdAb in sandwich assays for ricin detection. We employed a combination of consensus sequence mutagenesis and the addition of a non-canonical disulfide bond to further enhance the thermal stability of F6 to 85 °C. It is advantageous to have a choice of recognition reagents when developing assays. This work resulted in defining an additional pair of highly thermal stable sdAbs for the sensitive detection of ricin.
      PubDate: 2017-02-02
      DOI: 10.3390/antib6010003
      Issue No: Vol. 6, No. 1 (2017)
  • Antibodies, Vol. 6, Pages 4: Neutrophil Extracellular Traps,
           Antiphospholipid Antibodies and Treatment

    • Authors: Jessica Bravo-Barrera, Maria Kourilovitch, Claudio Galarza-Maldonado
      First page: 4
      Abstract: Neutrophil extracellular traps (NETs) are a network of extracellular fibers, compounds of chromatin, neutrophil DNA and histones, which are covered with antimicrobial enzymes with granular components. Autophagy and the production of reactive oxygen species (ROS) by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase are essential in the formation of NETs. There is increasing evidence that suggests that autoantibodies against beta-2-glycoprotein-1 (B2GP1) induce NETs and enhance thrombosis. Past research on new mechanisms of thrombosis formation in antiphospholipid syndrome (APS) has elucidated the pharmacokinetics of the most common medication in the treatment of the disease.
      PubDate: 2017-03-06
      DOI: 10.3390/antib6010004
      Issue No: Vol. 6, No. 1 (2017)
  • Antibodies, Vol. 6, Pages 5: Epitope Specificity of Anti-Citrullinated
           Protein Antibodies

    • Authors: Nicole Trier, Gunnar Houen
      First page: 5
      Abstract: Anti-citrullinated protein antibodies are primarily associated with a progressive course in the autoimmune disease rheumatoid arthritis, a disease with a chronic and inflammatory nature. These antibodies do not appear to have any strict dependency for reactivity except from the presence of the non-genetically encoded amino acid citrulline, which is the result of a posttranslational modification, catalyzed by calcium-dependent peptidylarginine deiminase enzymes. Nevertheless, several amino acids surrounding the citrulline residue notably influence antibody reactivity, especially with a central-Cit-Gly-motif being essential for antibody reactivity. Most importantly, these antibodies have been proposed to be divided into two groups, based on their ability to recognize multiple citrullinated peptides. Thus, an “overlapping” antibody group, which appears to recognize several citrullinated peptides, and a “non-overlapping” antibody group, which only recognizes a limited number of citrullinated peptides, have been proposed. Based on these findings, we suggest that antibodies recognizing several citrullinated targets, also referred to as cross-reactive antibodies, primarily are backbone-dependent, whereas less cross-reactive antibodies primarily depend on the side chains of the amino acids comprising the epitopes for stable antibody-antigen interactions, which reduces the degree of cross-reactivity significantly. Clarifying the reactivity pattern of anti-citrullinated protein antibodies may contribute to determining their true nature of origin.
      PubDate: 2017-03-08
      DOI: 10.3390/antib6010005
      Issue No: Vol. 6, No. 1 (2017)
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
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Fax: +00 44 (0)131 4513327
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