Next Issue
Previous Issue

Table of Contents

Antibodies, Volume 7, Issue 2 (June 2018)

  • Issues are regarded as officially published after their release is announced to the table of contents alert mailing list.
  • You may sign up for e-mail alerts to receive table of contents of newly released issues.
  • PDF is the official format for papers published in both, html and pdf forms. To view the papers in pdf format, click on the "PDF Full-text" link, and use the free Adobe Readerexternal link to open them.
View options order results:
result details:
Displaying articles 1-6
Export citation of selected articles as:
Open AccessArticle Allosteric Effects between the Antibody Constant and Variable Regions: A Study of IgA Fc Mutations on Antigen Binding
Antibodies 2018, 7(2), 20; https://doi.org/10.3390/antib7020020
Received: 14 May 2018 / Revised: 2 June 2018 / Accepted: 5 June 2018 / Published: 7 June 2018
Cited by 1 | Viewed by 748 | PDF Full-text (1852 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Therapeutic antibodies have shifted the paradigm of disease treatments from small molecules to biologics, especially in cancer therapy. Despite the increasing number of antibody candidates, much remains unknown about the antibody and how its various regions interact. Recent findings showed that the antibody
[...] Read more.
Therapeutic antibodies have shifted the paradigm of disease treatments from small molecules to biologics, especially in cancer therapy. Despite the increasing number of antibody candidates, much remains unknown about the antibody and how its various regions interact. Recent findings showed that the antibody constant region can govern localization effects that are useful in reducing side effects due to systemic circulation by the commonly used IgG isotypes. Given their localized mucosal effects, IgA antibodies are increasingly promising therapeutic biologics. While the antibody Fc effector cell activity has been a focus point, recent research showed that the Fc could also influence antigen binding, challenging the conventional idea of region-specific antibody functions. To investigate this, we analysed the IgA antibody constant region and its distal effects on the antigen binding regions using recombinant Pertuzumab IgA1 and IgA2 variants. We found that mutations in the C-region reduced Her2 binding experimentally, and computational structural analysis showed that allosteric communications were highly dependent on the antibody hinge, providing strong evidence that we should consider antibodies as whole proteins rather than a sum of functional regions. Full article
(This article belongs to the collection Computational Antibody and Antigen Design)
Figures

Graphical abstract

Open AccessReview Anti-Drug Antibodies: Emerging Approaches to Predict, Reduce or Reverse Biotherapeutic Immunogenicity
Antibodies 2018, 7(2), 19; https://doi.org/10.3390/antib7020019
Received: 9 April 2018 / Revised: 25 May 2018 / Accepted: 29 May 2018 / Published: 31 May 2018
Cited by 1 | Viewed by 1024 | PDF Full-text (1451 KB) | HTML Full-text | XML Full-text
Abstract
The development of anti-drug antibodies (ADAs) following administration of biotherapeutics to patients is a vexing problem that is attracting increasing attention from pharmaceutical and biotechnology companies. This serious clinical problem is also spawning creative research into novel approaches to predict, avoid, and in
[...] Read more.
The development of anti-drug antibodies (ADAs) following administration of biotherapeutics to patients is a vexing problem that is attracting increasing attention from pharmaceutical and biotechnology companies. This serious clinical problem is also spawning creative research into novel approaches to predict, avoid, and in some cases even reverse such deleterious immune responses. CD4+ T cells are essential players in the development of most ADAs, while memory B-cell and long-lived plasma cells amplify and maintain these responses. This review summarizes methods to predict and experimentally identify T-cell and B-cell epitopes in therapeutic proteins, with a particular focus on blood coagulation factor VIII (FVIII), whose immunogenicity is clinically significant and is the subject of intensive current research. Methods to phenotype ADA responses in humans are described, including T-cell stimulation assays, and both established and novel approaches to determine the titers, epitopes and isotypes of the ADAs themselves. Although rational protein engineering can reduce the immunogenicity of many biotherapeutics, complementary, novel approaches to induce specific tolerance, especially during initial exposures, are expected to play significant roles in future efforts to reduce or reverse these unwanted immune responses. Full article
(This article belongs to the Special Issue Analytical Methodologies for Antibodies)
Figures

Figure 1

Open AccessReview IgG Antibody 3D Structures and Dynamics
Antibodies 2018, 7(2), 18; https://doi.org/10.3390/antib7020018
Received: 8 February 2018 / Revised: 13 April 2018 / Accepted: 16 April 2018 / Published: 19 April 2018
Cited by 2 | Viewed by 2343 | PDF Full-text (6155 KB) | HTML Full-text | XML Full-text
Abstract
Antibodies are vital for human health because of their ability to function as nature’s drugs by protecting the body from infection. In recent decades, antibodies have been used as pharmaceutics for targeted therapy in patients with cancer, autoimmune diseases, and cardiovascular diseases. Capturing
[...] Read more.
Antibodies are vital for human health because of their ability to function as nature’s drugs by protecting the body from infection. In recent decades, antibodies have been used as pharmaceutics for targeted therapy in patients with cancer, autoimmune diseases, and cardiovascular diseases. Capturing the dynamic structure of antibodies and characterizing antibody fluctuation is critical for gaining a deeper understanding of their structural characteristics and for improving drug development. Current techniques for studying three-dimensional (3D) structural heterogeneity and variability of proteins have limitations in ascertaining the dynamic structural behavior of antibodies and antibody-antigen complexes. Here, we review current techniques used to study antibody structures with a focus on the recently developed individual-particle electron tomography (IPET) technique. IPET, as a particle-by-particle methodology for 3D structural characterization, has shown advantages in studying structural variety and conformational changes of antibodies, providing direct imaging data for biomolecular engineering to improve development and clinical application of synthetic antibodies. Full article
(This article belongs to the Special Issue Analytical Methodologies for Antibodies)
Figures

Figure 1

Open AccessEditorial Special Issue: Monoclonal Antibodies
Antibodies 2018, 7(2), 17; https://doi.org/10.3390/antib7020017
Received: 27 March 2018 / Revised: 8 April 2018 / Accepted: 9 April 2018 / Published: 10 April 2018
Viewed by 838 | PDF Full-text (157 KB) | HTML Full-text | XML Full-text
Abstract
Monoclonal antibodies are utilized in clinical practice for the treatment of various diseases including cancer, autoimmunity, metabolic and infectious diseases [...]
Full article
(This article belongs to the Special Issue Monoclonal Antibodies) Printed Edition available
Open AccessReview Small-Format Drug Conjugates: A Viable Alternative to ADCs for Solid Tumours?
Antibodies 2018, 7(2), 16; https://doi.org/10.3390/antib7020016
Received: 16 February 2018 / Revised: 7 March 2018 / Accepted: 8 March 2018 / Published: 31 March 2018
Cited by 3 | Viewed by 1485 | PDF Full-text (1022 KB) | HTML Full-text | XML Full-text
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
[...] Read more.
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. Full article
(This article belongs to the Special Issue Antibody Drug Conjugates)
Figures

Graphical abstract

Open AccessArticle Hydrophilic Auristatin Glycoside Payload Enables Improved Antibody-Drug Conjugate Efficacy and Biocompatibility
Antibodies 2018, 7(2), 15; https://doi.org/10.3390/antib7020015
Received: 15 December 2017 / Revised: 1 March 2018 / Accepted: 5 March 2018 / Published: 22 March 2018
Cited by 2 | Viewed by 1387 | PDF Full-text (2022 KB) | HTML Full-text | XML Full-text | Supplementary Files
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
[...] Read more.
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. Full article
(This article belongs to the Special Issue Antibody Drug Conjugates)
Figures

Figure 1

Back to Top