Monoclonal Antibody-Directed Therapy

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

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 76926

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors


E-Mail Website
Guest Editor
School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
Interests: development of vaccines; therapeutic monoclonal antibodies (mAbs); stabilization and formulation of vaccines and mAbs; nanoparticles; protein folding and aggregation
Special Issues, Collections and Topics in MDPI journals

E-Mail
Guest Editor
Exploratory Medicine & Pharmacology, Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN 46225, USA
Interests: monoclonal antibodies; ADCs; bispecifics; fusion proteins; antibody engineering; drug disposition; distribution; pharmacokinetics; modeling and simulation; physical–chemical characterization; mechanisms influencing clearance of antibody products
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The unparalleled specificity and high efficacy of monoclonal antibodies (mAbs) make them the most desirable products as biological medicines. They are amongst the top-selling drugs globally and their market size continues to grow annually. There are only about 70 mAb products on the market currently, but considering the hundreds that are in clinical trials and the new advancements in this field, such as the development of biosimilars, their market share is expected to increase substantially in the near future.

Over the years, different types of mAb products have been developed, including full-size mAbs, antibody fragments, antibody-drug-conjugates (ADC) and bispecifics, but full-size mAbs still dominate the market. In addition, new approaches such as PEGylation or the hyperglycosylation of constant domains of mAbs and other forms of antibodies such as single domain antibodies (nanobodies) and antibody-targeted nanoparticles have also been frequently explored and they seem to be promising, but these products are yet to receive approvals and reach the market.

The majority of biologics, in particular mAbs, are expensive due to the high costs associated with their development and manufacturing, and thus their similar follow-on counterparts—biosimilars—are expected to be very attractive to many consumers because of their affordability. The development of biosimilars has recently become possible for many blockbuster biologics owing to the loss of their patent protection and updates in regulatory guidelines.

Some of the antibody products are closely related to the reference product, but because they have superior characteristics compared to the former, they are called ‘biobetters’. These next-generation products are not defined well at the moment, but perhaps some existing products such as ADCs, bispecifics, and PEGylated or hyperglycosylated versions of certain products can be called biobetters. Biobetters may display improved efficacy/specificity, bind to more than one target or tackle some commonly observed physical–chemical issues such as protein aggregation. Advances in connecting the mechanisms influencing the disposition and pharmacokinetics of mAb products will continue to augment the discovery and development of antibody products. Immunogenicity and immunogenic potential remains a key space for the optimization of antibody products as therapeutic modalities.   

These new developments and other advances such as in silico methods employed to study and/or predict protein–protein interactions, require frequent updates in the literature and necessitates the publishing of a Special Issue journal such as this one. We strongly feel this is a timely commitment and would like to invite researchers from both academia and industry to submit their novel mAb therapy work for this issue in order to capture the new developments that have transpired as well as covering established concepts in this exciting field. In this Special Issue we will consider the following topics: mAb therapeutics, novel forms of antibody products, optimization or mAbs with experimental or computational methods including novel pharmacokinetic modeling and simulation approaches, advances in the pharmacokinetic characterization, disposition, biodistribution and clearance of antibody products, approaches towards immunogenicity prediction/characterization and new topics including but not limited to bispecifics, ADCs, nanobodies and antibody-targeted nanoparticles.

Assoc. Prof. Dr. Veysel Kayser
Dr. Amita Datta-Mannan
Guest Editors

Manuscript Submission Information

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

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

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Monoclonal antibody (mAb) therapies
  • Antibody medicines
  • Antibody drug conjugates (ADCs)
  • Bispecific and multispecific antibodies
  • Next-generation biologics
  • Follow-on biologics
  • Single-domain antibodies—nanobodies
  • Optimization of antibody products
  • Formulation of mAbs
  • Biosimilars
  • Biobetters
  • Antibody engineering
  • Antibody pharmacokinetics
  • Antibody distribution in vivo and in vitro
  • Modeling and simulation of antibody clearance
  • Physical–chemical characterization of antibody products
  • Mechanisms influencing antibody clearance

Published Papers (6 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Research

Jump to: Review

16 pages, 2068 KiB  
Article
Characterization of Co-Formulated High-Concentration Broadly Neutralizing Anti-HIV-1 Monoclonal Antibodies for Subcutaneous Administration
by Vaneet K. Sharma, Bijay Misra, Kevin T. McManus, Sreenivas Avula, Kaliappanadar Nellaiappan, Marina Caskey, Jill Horowitz, Michel C. Nussenzweig, Michael S. Seaman, Indu Javeri and Antu K. Dey
Antibodies 2020, 9(3), 36; https://0-doi-org.brum.beds.ac.uk/10.3390/antib9030036 - 29 Jul 2020
Cited by 8 | Viewed by 6340
Abstract
The discovery of numerous potent and broad neutralizing antibodies (bNAbs) against Human Immunodeficiency Virus type 1 (HIV-1) envelope glycoprotein has invigorated the potential of using them as an effective preventative and therapeutic agent. The majority of the anti-HIV-1 antibodies, currently under clinical investigation, [...] Read more.
The discovery of numerous potent and broad neutralizing antibodies (bNAbs) against Human Immunodeficiency Virus type 1 (HIV-1) envelope glycoprotein has invigorated the potential of using them as an effective preventative and therapeutic agent. The majority of the anti-HIV-1 antibodies, currently under clinical investigation, are formulated singly for intra-venous (IV) infusion. However, due to the high degree of genetic variability in the case of HIV-1, a single broad neutralizing antibody will likely not be sufficient to protect against the broad range of viral isolates. To that end, delivery of two or more co-formulated bnAbs against HIV-1 in a single subcutaneous (SC) injection is highly desired. We, therefore, co-formulated two anti-HIV bnAbs, 3BNC117-LS and 10-1074-LS, to a total concentration of 150 mg/mL for SC administration and analyzed them using a panel of analytical techniques. Chromatographic based methods, such as RP-HPLC, CEX-HPLC, SEC-HPLC, were developed to ensure separation and detection of each antibody in the co-formulated sample. In addition, we used a panel of diverse pseudoviruses to detect the functionality of individual antibodies in the co-formulation. We also used these methods to test the stability of the co-formulated antibodies and believe that such an approach can support future efforts towards the formulation and characterization of multiple high-concentration antibodies for SC delivery. Full article
(This article belongs to the Special Issue Monoclonal Antibody-Directed Therapy)
Show Figures

Figure 1

Review

Jump to: Research

17 pages, 1309 KiB  
Review
Discovery Strategies to Maximize the Clinical Potential of T-Cell Engaging Antibodies for the Treatment of Solid Tumors
by Vladimir Voynov, Paul J. Adam, Andrew E. Nixon and Justin M. Scheer
Antibodies 2020, 9(4), 65; https://0-doi-org.brum.beds.ac.uk/10.3390/antib9040065 - 18 Nov 2020
Cited by 13 | Viewed by 6636
Abstract
T-cell Engaging bispecific antibodies (TcEs) that can re-direct cytotoxic T-cells to kill cancer cells have been validated in clinical studies. To date, the clinical success with these agents has mainly been seen in hematologic tumor indications. However, an increasing number of TcEs are [...] Read more.
T-cell Engaging bispecific antibodies (TcEs) that can re-direct cytotoxic T-cells to kill cancer cells have been validated in clinical studies. To date, the clinical success with these agents has mainly been seen in hematologic tumor indications. However, an increasing number of TcEs are currently being developed to exploit the potent mode-of-action to treat solid tumor indications, which is more challenging in terms of tumor-cell accessibility and the complexity of the tumor microenvironment (TME). Of particular interest is the potential of TcEs as an immunotherapeutic approach for the treatment of non-immunogenic (often referred to as cold) tumors that do not respond to checkpoint inhibitors such as programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) antibodies. This has led to considerable discovery efforts for, firstly, the identification of tumor selective targeting approaches that can safely re-direct cytotoxic T-cells to cancer cells, and, secondly, bispecific antibodies and their derivatives with drug-like properties that promote a potent cytolytic synapse between T-cells and tumor cells, and in the most advanced TcEs, have IgG-like pharmacokinetics for dosing convenience. Based on encouraging pre-clinical data, a growing number of TcEs against a broad range of targets, and using an array of different molecular structures have entered clinical studies for solid tumor indications, and the first clinical data is beginning to emerge. This review outlines the different approaches that have been taken to date in addressing the challenges of exploiting the TcE mode-of-action for a broad range of solid indications, as well as opportunities for future discovery potential. Full article
(This article belongs to the Special Issue Monoclonal Antibody-Directed Therapy)
Show Figures

Figure 1

23 pages, 3152 KiB  
Review
Antibodies Inhibiting the Type III Secretion System of Gram-Negative Pathogenic Bacteria
by Julia A. Hotinger and Aaron E. May
Antibodies 2020, 9(3), 35; https://0-doi-org.brum.beds.ac.uk/10.3390/antib9030035 - 27 Jul 2020
Cited by 16 | Viewed by 12221
Abstract
Pathogenic bacteria are a global health threat, with over 2 million infections caused by Gram-negative bacteria every year in the United States. This problem is exacerbated by the increase in resistance to common antibiotics that are routinely used to treat these infections, creating [...] Read more.
Pathogenic bacteria are a global health threat, with over 2 million infections caused by Gram-negative bacteria every year in the United States. This problem is exacerbated by the increase in resistance to common antibiotics that are routinely used to treat these infections, creating an urgent need for innovative ways to treat and prevent virulence caused by these pathogens. Many Gram-negative pathogenic bacteria use a type III secretion system (T3SS) to inject toxins and other effector proteins directly into host cells. The T3SS has become a popular anti-virulence target because it is required for pathogenesis and knockouts have attenuated virulence. It is also not required for survival, which should result in less selective pressure for resistance formation against T3SS inhibitors. In this review, we will highlight selected examples of direct antibody immunizations and the use of antibodies in immunotherapy treatments that target the bacterial T3SS. These examples include antibodies targeting the T3SS of Pseudomonas aeruginosa, Yersinia pestis, Escherichia coli, Salmonella enterica, Shigella spp., and Chlamydia trachomatis. Full article
(This article belongs to the Special Issue Monoclonal Antibody-Directed Therapy)
Show Figures

Figure 1

20 pages, 3451 KiB  
Review
Principles of N-Linked Glycosylation Variations of IgG-Based Therapeutics: Pharmacokinetic and Functional Considerations
by Souad Boune, Peisheng Hu, Alan L. Epstein and Leslie A. Khawli
Antibodies 2020, 9(2), 22; https://0-doi-org.brum.beds.ac.uk/10.3390/antib9020022 - 10 Jun 2020
Cited by 63 | Viewed by 18509
Abstract
The development of recombinant therapeutic proteins has been a major revolution in modern medicine. Therapeutic-based monoclonal antibodies (mAbs) are growing rapidly, providing a potential class of human pharmaceuticals that can improve the management of cancer, autoimmune diseases, and other conditions. Most mAbs are [...] Read more.
The development of recombinant therapeutic proteins has been a major revolution in modern medicine. Therapeutic-based monoclonal antibodies (mAbs) are growing rapidly, providing a potential class of human pharmaceuticals that can improve the management of cancer, autoimmune diseases, and other conditions. Most mAbs are typically of the immunoglobulin G (IgG) subclass, and they are glycosylated at the conserved asparagine position 297 (Asn-297) in the CH2 domain of the Fc region. Post-translational modifications here account for the observed high heterogeneity of glycoforms that may or not impact the stability, pharmacokinetics (PK), efficacy, and immunogenicity of mAbs. These modifications are also critical for the Fc receptor binding, and consequently, key antibody effector functions including antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Moreover, mAbs produced in non-human cells express oligosaccharides that are not normally found in serum IgGs might lead to immunogenicity issues when administered to patients. This review summarizes our understanding of the terminal sugar residues, such as mannose, sialic acids, fucose, or galactose, which influence therapeutic mAbs either positively or negatively in this regard. This review also discusses mannosylation, which has significant undesirable effects on the PK of glycoproteins, causing a decreased mAbs’ half-life. Moreover, terminal galactose residues can enhance CDC activities and Fc–C1q interactions, and core fucose can decrease ADCC and Fc–FcγRs binding. To optimize the therapeutic use of mAbs, glycoengineering strategies are used to reduce glyco-heterogeneity of mAbs, increase their safety profile, and improve the therapeutic efficacy of these important reagents. Full article
(This article belongs to the Special Issue Monoclonal Antibody-Directed Therapy)
Show Figures

Graphical abstract

27 pages, 2823 KiB  
Review
Antibody Conjugates-Recent Advances and Future Innovations
by Donmienne Leung, Jacqueline M. Wurst, Tao Liu, Ruben M. Martinez, Amita Datta-Mannan and Yiqing Feng
Antibodies 2020, 9(1), 2; https://0-doi-org.brum.beds.ac.uk/10.3390/antib9010002 - 08 Jan 2020
Cited by 76 | Viewed by 16838
Abstract
Monoclonal antibodies have evolved from research tools to powerful therapeutics in the past 30 years. Clinical success rates of antibodies have exceeded expectations, resulting in heavy investment in biologics discovery and development in addition to traditional small molecules across the industry. However, protein [...] Read more.
Monoclonal antibodies have evolved from research tools to powerful therapeutics in the past 30 years. Clinical success rates of antibodies have exceeded expectations, resulting in heavy investment in biologics discovery and development in addition to traditional small molecules across the industry. However, protein therapeutics cannot drug targets intracellularly and are limited to soluble and cell-surface antigens. Tremendous strides have been made in antibody discovery, protein engineering, formulation, and delivery devices. These advances continue to push the boundaries of biologics to enable antibody conjugates to take advantage of the target specificity and long half-life from an antibody, while delivering highly potent small molecule drugs. While the “magic bullet” concept produced the first wave of antibody conjugates, these entities were met with limited clinical success. This review summarizes the advances and challenges in the field to date with emphasis on antibody conjugation, linker-payload chemistry, novel payload classes, absorption, distribution, metabolism, and excretion (ADME), and product developability. We discuss lessons learned in the development of oncology antibody conjugates and look towards future innovations enabling other therapeutic indications. Full article
(This article belongs to the Special Issue Monoclonal Antibody-Directed Therapy)
Show Figures

Figure 1

23 pages, 3985 KiB  
Review
Current Advancements in Addressing Key Challenges of Therapeutic Antibody Design, Manufacture, and Formulation
by Vicki Sifniotis, Esteban Cruz, Barbaros Eroglu and Veysel Kayser
Antibodies 2019, 8(2), 36; https://0-doi-org.brum.beds.ac.uk/10.3390/antib8020036 - 03 Jun 2019
Cited by 42 | Viewed by 14470
Abstract
Therapeutic antibody technology heavily dominates the biologics market and continues to present as a significant industrial interest in developing novel and improved antibody treatment strategies. Many noteworthy advancements in the last decades have propelled the success of antibody development; however, there are still [...] Read more.
Therapeutic antibody technology heavily dominates the biologics market and continues to present as a significant industrial interest in developing novel and improved antibody treatment strategies. Many noteworthy advancements in the last decades have propelled the success of antibody development; however, there are still opportunities for improvement. In considering such interest to develop antibody therapies, this review summarizes the array of challenges and considerations faced in the design, manufacture, and formulation of therapeutic antibodies, such as stability, bioavailability and immunological engagement. We discuss the advancement of technologies that address these challenges, highlighting key antibody engineered formats that have been adapted. Furthermore, we examine the implication of novel formulation technologies such as nanocarrier delivery systems for the potential to formulate for pulmonary delivery. Finally, we comprehensively discuss developments in computational approaches for the strategic design of antibodies with modulated functions. Full article
(This article belongs to the Special Issue Monoclonal Antibody-Directed Therapy)
Show Figures

Graphical abstract

Back to TopTop