Topical Collection "Research on Monoclonal Antibodies and Antibody Engineering"

Editor

Dr. Tatsuya Yamazaki
E-Mail Website
Collection Editor
Department of Microbiology and Immunology, School of Medicine, Aichi Medical University, Aichi 480-1195, Japan
Interests: antibody gene-based prophylaxis and therapy; physiology of antibody; DNA immunization; gene therapy; gene transfer; vaccine; adjuvant; influenza virus; immunology; virology

Topical Collection Information

Dear Colleagues,

Our Special Issue, focuses on passive immune prophylaxis and therapy using monoclonal antibodies (mAbs) for a variety of diseases such as infection, cancer, and autoimmune disease. Passive immunization has a long history, dating back to the production of anti-tetanus and anti-diphtheria serum in the late 19th century by Kitasato and Behring. Inoculation with neutralizing antibodies is generally expected to induce a rapid and potent protective and therapeutic effect, independent of the individual’s immunocompetence. As you well know, current mAb-based products have attracted much attention for being one of the most effective molecular target drugs, and have also financially succeeded in developed markets. However, several obstacles hinder the widespread use of antibody drugs, such as a high production cost, the necessity of weekly or biweekly infusions due to short half-life (approximately 20 days), quality control, laborious development of the effective mAbs, shedding the target, antigenic variations, and unwanted side effects.

To address the above problems, and to share your interesting knowledge in the field of passive immunization, we are inviting you to submit  an original research or review to this Special Issue on one of the following topics:

(i) The methods of administration; e.g., antibody gene based-passive prophylaxis or therapy.

(ii) Antibody engineering; e.g., bispecific T-cell engager (BiTE), camelid variable domain of heavy chain only antibody (VHH), multivalent multidomain antibody (MDAb), defucosylated antibodies, and engineered Fc domain.

(iii) How to develop the effective mAbs; e.g., single-cell RNA sequencing (scRNA-seq), DNA immunization, adjuvant, double trans-chromosomic mouse, and ex vivo affinity maturation.

We also welcome to general remarks or details about your interesting mAbs on the following topic:

(iv) Prophylactic or therapeutic mAb against virus (e.g., influenza virus, SARS-CoV-2, HIV, dengue virus, and RS virus), bacteria (e.g., Clostridium difficile and Bacillus anthracis), parasite (e.g. malaria), fungus (e.g. Aspergillus), cancer, autoimmune disease, allergy, and obesity.

We are looking forward to your interesting manuscript.

Dr. Tatsuya Yamazaki
Collection Editor 

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 papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the collection 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. Vaccines is an international peer-reviewed open access monthly 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 2200 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

  • passive immunization
  • antibody gene-based passive prophylaxis or therapy
  • antibody engineering
  • monoclonal antibody
  • infectious diseases
  • cancer
  • autoimmune diseases
  • allergy
  • obesity

Published Papers (15 papers)

2021

Jump to: 2020

Article
Anti-IAPP Monoclonal Antibody Improves Clinical Symptoms in a Mouse Model of Type 2 Diabetes
Vaccines 2021, 9(11), 1316; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9111316 - 12 Nov 2021
Viewed by 420
Abstract
Type 2 Diabetes Mellitus (T2DM) is a chronic progressive disease, defined by insulin resistance and insufficient insulin secretion to maintain normoglycemia. Amyloidogenic aggregates are a hallmark of T2DM patients; they are cytotoxic for the insulin producing β-cells, and cause inflammasome-dependent secretion of IL-1β. [...] Read more.
Type 2 Diabetes Mellitus (T2DM) is a chronic progressive disease, defined by insulin resistance and insufficient insulin secretion to maintain normoglycemia. Amyloidogenic aggregates are a hallmark of T2DM patients; they are cytotoxic for the insulin producing β-cells, and cause inflammasome-dependent secretion of IL-1β. To avoid the associated β-cell loss and inflammation in advanced stage T2DM, we developed a novel monoclonal therapy targeting the major component of aggregates, islet amyloid polypeptide (IAPP). The here described monoclonal antibody (mAb) m81, specific for oligomeric and fibrils, but not for soluble free IAPP, is able to prevent oligomer growth and aggregate formation in vitro, and blocks islet inflammation and disease progression in vivo. Collectively, our data show that blocking fibril formation and prevention of new amyloidogenic aggregates by monoclonal antibody therapy may be a potential therapy for T2DM. Full article
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Review
Antibody-Drug Conjugates: Functional Principles and Applications in Oncology and Beyond
Vaccines 2021, 9(10), 1111; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9101111 - 29 Sep 2021
Cited by 1 | Viewed by 802
Abstract
In the era of precision medicine, antibody-based therapeutics are rapidly enriched with emerging advances and new proof-of-concept formats. In this context, antibody-drug conjugates (ADCs) have evolved to merge the high selectivity and specificity of monoclonal antibodies (mAbs) with the cytotoxic potency of attached [...] Read more.
In the era of precision medicine, antibody-based therapeutics are rapidly enriched with emerging advances and new proof-of-concept formats. In this context, antibody-drug conjugates (ADCs) have evolved to merge the high selectivity and specificity of monoclonal antibodies (mAbs) with the cytotoxic potency of attached payloads. So far, ten ADCs have been approved by FDA for oncological indications and many others are currently being tested in clinical and preclinical level. This paper summarizes the essential components of ADCs, from their functional principles and structure up to their limitations and resistance mechanisms, focusing on all latest bioengineering breakthroughs such as bispecific mAbs, dual-drug platforms as well as novel linkers and conjugation chemistries. In continuation of our recent review on anticancer implication of ADC’s technology, further insights regarding their potential usage outside of the oncological spectrum are also presented. Better understanding of immunoconjugates could maximize their efficacy and optimize their safety, extending their use in everyday clinical practice. Full article
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Article
Human Transbodies to Reverse Transcriptase Connection Subdomain of HIV-1 Gag-Pol Polyprotein Reduce Infectiousness of the Virus Progeny
Vaccines 2021, 9(8), 893; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9080893 - 12 Aug 2021
Cited by 1 | Viewed by 639
Abstract
HIV-1 progeny are released from infected cells as immature particles that are unable to infect new cells. Gag-Pol polyprotein dimerization via the reverse transcriptase connection domain (RTCDs) is pivotal for proper activation of the virus protease (PR protein) in an early event of [...] Read more.
HIV-1 progeny are released from infected cells as immature particles that are unable to infect new cells. Gag-Pol polyprotein dimerization via the reverse transcriptase connection domain (RTCDs) is pivotal for proper activation of the virus protease (PR protein) in an early event of the progeny virus maturation process. Thus, the RTCD is a potential therapeutic target for a broadly effective anti-HIV agent through impediment of virus maturation. In this study, human single-chain antibodies (HuscFvs) that bound to HIV-1 RTCD were generated using phage display technology. Computerized simulation guided the selection of the transformed Escherichia coli-derived HuscFvs that bound to the RTCD dimer interface. The selected HuscFvs were linked molecularly to human-derived-cell-penetrating peptide (CPP) to make them cell-penetrable (i.e., become transbodies). The CPP-HuscFvs/transbodies produced by a selected transformed E. coli clone were tested for anti-HIV-1 activity. CPP-HuscFvs of transformed E. coli clone 11 (CPP-HuscFv11) that presumptively bound at the RTCD dimer interface effectively reduced reverse transcriptase activity in the newly released virus progeny. Infectiousness of the progeny viruses obtained from CPP-HuscFv11-treated cells were reduced by a similar magnitude to those obtained from protease/reverse transcriptase inhibitor-treated cells, indicating anti-HIV-1 activity of the transbodies. The CPP-HuscFv11/transbodies to HIV-1 RTCD could be an alternative, anti-retroviral agent for long-term HIV-1 treatment. Full article
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Article
Anti-CD47 Monoclonal Antibody–Drug Conjugate: A Targeted Therapy to Treat Triple-Negative Breast Cancers
Vaccines 2021, 9(8), 882; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9080882 - 10 Aug 2021
Cited by 2 | Viewed by 1424
Abstract
Triple-negative breast cancers (TNBCs) are frequently recurrent due to the development of drug resistance post chemotherapy. Both the existing literature and our study found that surface receptor CD47 (cluster of differentiation 47) was upregulated in chemotherapy-treated TNBC cells. The goal of this study [...] Read more.
Triple-negative breast cancers (TNBCs) are frequently recurrent due to the development of drug resistance post chemotherapy. Both the existing literature and our study found that surface receptor CD47 (cluster of differentiation 47) was upregulated in chemotherapy-treated TNBC cells. The goal of this study was to develop a monoclonal antibody (mAb)-based targeting strategy to treat TNBC after standard treatment. Specifically, a new mAb that targets the extracellular domain of receptor CD47 was developed using hybridoma technology and produced in fed-batch culture. Flow cytometry, confocal microscopy, and in vivo imaging system (IVIS) showed that the anti-CD47 mAb effectively targeted human and mouse TNBC cells and xenograft models with high specificity. The antibody–drug conjugate (ADC) carrying mertansine was constructed and demonstrated higher potency with reduced IC50 in TNBC cells than did the free drug and significantly inhibited tumor growth post gemcitabine treatment in MDA-MB-231 xenograft NSG model. Finally, whole blood analysis indicated that the anti-CD47 mAb had no general immune toxicity, flow cytometry analysis of lymph nodes revealed an increase of CD69+ NK, CD11c+ DC, and CD4+ T cells, and IHC staining showed tumoral infiltration of macrophage in the 4T1 xenograft BALB/cJ model. This study demonstrated that targeting CD47 with ADC has great potential to treat TNBCs as a targeted therapy. Full article
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Article
Rabbit Monoclonal Antibody Specifically Recognizing a Linear Epitope in the RBD of SARS-CoV-2 Spike Protein
Vaccines 2021, 9(8), 829; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9080829 - 28 Jul 2021
Viewed by 730
Abstract
To date, SARS-CoV-2 pandemic has caused more than 188 million infections and 4.06 million deaths worldwide. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein has been regarded as an important target for vaccine and therapeutics development because it plays a key role [...] Read more.
To date, SARS-CoV-2 pandemic has caused more than 188 million infections and 4.06 million deaths worldwide. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein has been regarded as an important target for vaccine and therapeutics development because it plays a key role in binding the human cell receptor ACE2 that is required for viral entry. However, it is not easy to detect RBD in Western blot using polyclonal antibody, suggesting that RBD may form a complicated conformation under native condition and bear rare linear epitope. So far, no linear epitope on RBD is reported. Thus, a monoclonal antibody (mAb) that recognizes linear epitope on RBD will become valuable. In the present study, an RBD-specific rabbit antibody named 9E1 was isolated from peripheral blood mononuclear cells (PBMC) of immunized rabbit by RBD-specific single B cell sorting and mapped to a highly conserved linear epitope within twelve amino acids 480CNGVEGFNCYFP491 on RBD. 9E1 works well in Western blot on S protein and immunohistochemistry on the SARS-CoV-2 infected tissue sections. The results demonstrated that 9E1 can be used as a useful tool for pathological and functional studies of SARS-CoV-2. Full article
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Review
Detection of Urinary Antibodies and Its Application in Epidemiological Studies for Parasitic Diseases
Vaccines 2021, 9(7), 778; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9070778 - 12 Jul 2021
Viewed by 1187
Abstract
For epidemiological studies of infectious diseases, pathogen-specific antibody levels in an area give us essential and appropriate information. The antibodies against pathogens are usually detected in blood, the drawing of which inconveniences people. Collection of blood increases the risk of accidental infections through [...] Read more.
For epidemiological studies of infectious diseases, pathogen-specific antibody levels in an area give us essential and appropriate information. The antibodies against pathogens are usually detected in blood, the drawing of which inconveniences people. Collection of blood increases the risk of accidental infections through blood, and it is difficult to obtain the participation of the target populations, especially the younger generation. On the other hand, urine samples, which contain a high enough level of antibodies for ELISA, can be harmlessly and easily collected and therefore have been used for epidemiological studies for diseases. The antibody examination of urine has been used for the epidemiology of parasitic diseases with a high sensitivity and specificity of serum samples. In this paper, we reviewed antibody assays with urine for seven parasitic diseases that urine diagnostic methods have reported in the past, and these are important infections included in NTDs, caused, for example, by Leishmania donovani, Wuchereria bancrofti, Schistosoma japonicum, Paragonimus westermani, Echinococcus granulosus, Echinococcus multilocularis, Strongyloides stercoralis, and Opisthorchis viverrini. The easy and safe urine surveillance system might be an admirable tool for future epidemiological studies for infectious diseases. Full article
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Article
Epitope–Paratope Interaction of a Neutralizing Human Anti-Hepatitis B Virus PreS1 Antibody That Recognizes the Receptor-Binding Motif
Vaccines 2021, 9(7), 754; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9070754 - 07 Jul 2021
Viewed by 821
Abstract
Hepatitis B virus (HBV) is a global health burden that causes acute and chronic hepatitis. To develop an HBV-neutralizing antibody that effectively prevents HBV infection, we previously generated a human anti-preS1 monoclonal antibody (1A8) that binds to genotypes A–D and validated its HBV-neutralizing [...] Read more.
Hepatitis B virus (HBV) is a global health burden that causes acute and chronic hepatitis. To develop an HBV-neutralizing antibody that effectively prevents HBV infection, we previously generated a human anti-preS1 monoclonal antibody (1A8) that binds to genotypes A–D and validated its HBV-neutralizing activity in vitro. In the present study, we aimed to determine the fine epitope and paratope of 1A8 to understand the mechanism of HBV neutralization. We performed alanine-scanning mutagenesis on the preS1 (aa 19–34, genotype C) and the heavy (HCDR) and light (LCDR) chain complementarity-determining regions. The 1A8 recognized the three residues (Leu22, Gly23, and Phe25) within the highly conserved receptor-binding motif (NPLGFFP) of the preS1, while four CDR residues of 1A8 were critical in antigen binding. Structural analysis of the epitope–paratope interaction by molecular modeling revealed that Leu100 in the HCDR3, Ala50 in the HCDR2, and Tyr96 in the LCDR3 closely interacted with Leu22, Gly23, and Phe25 of the preS1. Additionally, we found that 1A8 also binds to the receptor-binding motif (NPLGFLP) of infrequently occurring HBV. The results suggest that 1A8 may broadly and effectively block HBV entry and thus have potential as a promising candidate for the prevention and treatment of HBV infection. Full article
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Review
Therapeutic Potential of HLA-I Polyreactive mAbs Mimicking the HLA-I Polyreactivity and Immunoregulatory Functions of IVIg
Vaccines 2021, 9(6), 680; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9060680 - 21 Jun 2021
Cited by 1 | Viewed by 726
Abstract
HLA class-I (HLA-I) polyreactive monoclonal antibodies (mAbs) reacting to all HLA-I alleles were developed by immunizing mice with HLA-E monomeric, α-heavy chain (αHC) open conformers (OCs). Two mAbs (TFL-006 and TFL-007) were bound to the αHC’s coated on a solid matrix. The binding [...] Read more.
HLA class-I (HLA-I) polyreactive monoclonal antibodies (mAbs) reacting to all HLA-I alleles were developed by immunizing mice with HLA-E monomeric, α-heavy chain (αHC) open conformers (OCs). Two mAbs (TFL-006 and TFL-007) were bound to the αHC’s coated on a solid matrix. The binding was inhibited by the peptide 117AYDGKDY123, present in all alleles of the six HLA-I isoforms but masked by β2-microglobulin (β2-m) in intact HLA-I trimers (closed conformers, CCs). IVIg preparations administered to lower anti-HLA Abs in pre-and post-transplant patients have also shown HLA-I polyreactivity. We hypothesized that the mAbs that mimic IVIg HLA-I polyreactivity might also possess the immunomodulatory capabilities of IVIg. We tested the relative binding affinities of the mAbs and IVIg for both OCs and CCs and compared their effects on (a) the phytohemagglutinin (PHA)-activation T-cells; (b) the production of anti-HLA-II antibody (Ab) by B-memory cells and anti-HLA-I Ab by immortalized B-cells; and (c) the upregulation of CD4+, CD25+, and Fox P3+ T-regs. The mAbs bound only to OC, whereas IVIg bound to both CC and OC. The mAbs suppressed blastogenesis and proliferation of PHA-activated T-cells and anti-HLA Ab production by B-cells and expanded T-regs better than IVIg. We conclude that a humanized version of the TFL-mAbs could be an ideal, therapeutic IVIg-mimetic. Full article
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Review
The Relevance of Monoclonal Antibodies in the Treatment of COVID-19
Vaccines 2021, 9(6), 557; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9060557 - 26 May 2021
Cited by 1 | Viewed by 2261
Abstract
Major efforts have been made in the search for effective treatments since the outbreak of the COVID-19 infection in December 2019. Extensive research has been conducted on drugs that are already available and new treatments are also under development. Within this context, therapeutic [...] Read more.
Major efforts have been made in the search for effective treatments since the outbreak of the COVID-19 infection in December 2019. Extensive research has been conducted on drugs that are already available and new treatments are also under development. Within this context, therapeutic monoclonal antibodies (mAbs) have been the subject of widespread investigation focusing on two target-based groups, i.e., non-SARS-CoV-2 specific mAbs, that target immune system responses, and SARS-CoV-2 specific mAbs, designed to neutralize the virus protein structure. Here we review the latest literature about the use of mAbs in order to describe the state of the art of the clinical trials and the benefits of using these biotherapeutics in the treatment of COVID-19. The clinical trials considered in the present review include both observational and randomized studies. We begin by presenting the studies conducted using non-SARS-CoV-2 specific mAbs for treating different immune disorders that were already on the market. Within this group of mAbs, we focus particularly on anti-IL-6/IL-6R. This is followed by a discussion of the studies on SARS-CoV-2 specific mAbs. Our findings indicate that SARS-CoV-2 specific mAbs are significantly more effective than non-specific ones. Full article
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Review
Monoclonal Antibodies Targeting Surface-Exposed and Secreted Proteins from Staphylococci
Vaccines 2021, 9(5), 459; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9050459 - 04 May 2021
Cited by 3 | Viewed by 854
Abstract
Staphylococci (specifically Staphylococcus aureus and Staphylococcus epidermidis) are the causative agents of diseases ranging from superficial skin and soft tissue infections to severe conditions such as fatal pneumonia, bacteremia, sepsis and endocarditis. The widespread and indiscriminate use of antibiotics has led to [...] Read more.
Staphylococci (specifically Staphylococcus aureus and Staphylococcus epidermidis) are the causative agents of diseases ranging from superficial skin and soft tissue infections to severe conditions such as fatal pneumonia, bacteremia, sepsis and endocarditis. The widespread and indiscriminate use of antibiotics has led to serious problems of resistance to staphylococcal disease and has generated a renewed interest in alternative therapeutic agents such as vaccines and antibodies. Staphylococci express a large repertoire of surface and secreted virulence factors, which provide mechanisms (adhesion, invasion and biofilm development among others) for both bacterial survival in the host and evasion from innate and adaptive immunity. Consequently, the development of antibodies that target specific antigens would provide an effective protective strategy against staphylococcal infections. In this review, we report an update on efforts to develop anti-staphylococci monoclonal antibodies (and their derivatives: minibodies, antibody–antibiotic conjugates) and the mechanism by which such antibodies can help fight infections. We also provide an overview of mAbs used in clinical trials and highlight their therapeutic potential in various infectious contexts. Full article
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Article
Engineered Human Monoclonal scFv to Receptor Binding Domain of Ebolavirus
Vaccines 2021, 9(5), 457; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9050457 - 04 May 2021
Cited by 1 | Viewed by 821
Abstract
(1) Background: Ebolavirus (EBOV) poses as a significant threat for human health by frequently causing epidemics of the highly contagious Ebola virus disease (EVD). EBOV glycoprotein (GP), as a sole surface glycoprotein, needs to be cleaved in endosomes to fully expose a receptor-binding [...] Read more.
(1) Background: Ebolavirus (EBOV) poses as a significant threat for human health by frequently causing epidemics of the highly contagious Ebola virus disease (EVD). EBOV glycoprotein (GP), as a sole surface glycoprotein, needs to be cleaved in endosomes to fully expose a receptor-binding domain (RBD) containing a receptor-binding site (RBS) for receptor binding and genome entry into cytoplasm for replication. RBDs are highly conserved among EBOV species, so they are an attractive target for broadly effective anti-EBOV drug development. (2) Methods: Phage display technology was used as a tool to isolate human single-chain antibodies (HuscFv) that bind to recombinant RBDs from a human scFv (HuscFv) phage display library. The RBD-bound HuscFvs were fused with cell-penetrating peptide (CPP), and cell-penetrating antibodies (transbodies) were made, produced from the phage-infected E. coli clones and characterized. (3) Results: Among the HuscFvs obtained from phage-infected E. coli clones, HuscFvs of three clones, HuscFv4, HuscFv11, and HuscFv14, the non-cell-penetrable or cell-penetrable HuscFv4 effectively neutralized cellular entry of EBOV-like particles (VLPs). While all HuscFvs were found to bind cleaved GP (GPcl), their presumptive binding sites were markedly different, as determined by molecular docking. (4) Conclusions: The HuscFv4 could be a promising therapeutic agent against EBOV infection. Full article
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Article
Passive Immunity and Antibody Response Induced by Toxoplasma gondii VLP Immunization
Vaccines 2021, 9(5), 425; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9050425 - 23 Apr 2021
Cited by 2 | Viewed by 634
Abstract
Passive immunity can provide immediate protection against infectious pathogens. To date, only a few studies have investigated the effect of passive immunization against Toxoplasma gondii, and the use of immune sera acquired from VLP-vaccinated mice for passive immunity assessment remains unreported. In [...] Read more.
Passive immunity can provide immediate protection against infectious pathogens. To date, only a few studies have investigated the effect of passive immunization against Toxoplasma gondii, and the use of immune sera acquired from VLP-vaccinated mice for passive immunity assessment remains unreported. In this study, immune sera were produced by a single immunization with virus-like particles (VLPs) expressing the inner membrane complex (IMC), rhoptry protein 18 (ROP18), and microneme protein 8 (MIC8) of Toxoplasma gondii, with or without a CpG-ODN adjuvant. The passive immunization of immune sera conferred protection in mice, as indicated by their potent parasite-specific antibody response, lessened brain cyst counts, lower bodyweight loss, and enhanced survival. In order to confirm that the immune sera of the VLP-immunized mice were truly protective, the antibody responses and other immunological parameters were measured in the VLP-immunized mice. We found that VLP immunization induced higher levels of parasite-specific IgG, IgG subclass, and IgM antibody responses in the sera and intestines than in the controls. Enhanced Th1 and Th2-associated cytokines in the spleen, diminished brain cyst counts, and lessened body weight loss were found following T. gondii ME49 challenge infection. These results suggest that passive immunization with the immune sera acquired from VLP-vaccinated mice can confer adequate protection against T. gondii infection. Full article
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Review
Therapeutic Antibodies for the Treatment of Respiratory Tract Infections—Current Overview and Perspectives
Vaccines 2021, 9(2), 151; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9020151 - 13 Feb 2021
Cited by 1 | Viewed by 1831
Abstract
Respiratorytract infections (RTIs) are frequent and life-threatening diseases, accounting for several millions of deaths worldwide. RTIs implicate microorganisms, including viruses (influenza virus, coronavirus, respiratory syncytial virus (RSV)), bacteria (Pseudomonas aeruginosa, Streptococcus pneumoniae, Staphylococcus aureus and Bacillus anthracis) and fungi [...] Read more.
Respiratorytract infections (RTIs) are frequent and life-threatening diseases, accounting for several millions of deaths worldwide. RTIs implicate microorganisms, including viruses (influenza virus, coronavirus, respiratory syncytial virus (RSV)), bacteria (Pseudomonas aeruginosa, Streptococcus pneumoniae, Staphylococcus aureus and Bacillus anthracis) and fungi (Pneumocystis spp., Aspergillus spp. and very occasionally Candida spp.). The emergence of new pathogens, like the coronavirus SARS-CoV-2, and the substantial increase in drug resistance have highlighted the critical necessity to develop novel anti-infective molecules. In this context, antibodies (Abs) are becoming increasingly important in respiratory medicine and may fulfill the unmet medical needs of RTIs. However, development of Abs for treating infectious diseases is less advanced than for cancer and inflammatory diseases. Currently, only three Abs have been marketed for RTIs, namely, against pulmonary anthrax and RSV infection, while several clinical and preclinical studies are in progress. This article gives an overview of the advances in the use of Abs for the treatment of RTIs, based on the analysis of clinical studies in this field. It describes the Ab structure, function and pharmacokinetics, and discusses the opportunities offered by the various Ab formats, Ab engineering and co-treatment strategies. Including the most recent literature, it finally highlights the strengths, weaknesses and likely future trends of a novel anti-RTI Ab armamentarium. Full article
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Article
Identification of Two Novel Linear Neutralizing Epitopes within the Hexon Protein of Canine Adenovirus Using Monoclonal Antibodies
Vaccines 2021, 9(2), 135; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9020135 - 08 Feb 2021
Viewed by 1045
Abstract
Canine adenovirus (CAdV) has a high prevalence in canine populations. High affinity neutralizing antibodies against conserved epitopes can provide protective immunity against CAdV and protect against future outbreaks. In this study, we identified two CAdV-2-specific neutralizing monoclonal antibodies (mAbs), 2C1 and 7D7, which [...] Read more.
Canine adenovirus (CAdV) has a high prevalence in canine populations. High affinity neutralizing antibodies against conserved epitopes can provide protective immunity against CAdV and protect against future outbreaks. In this study, we identified two CAdV-2-specific neutralizing monoclonal antibodies (mAbs), 2C1 and 7D7, which recognized two linear-dependent epitopes. MAb 2C1 potently neutralized CAdV-2 with a 50% neutralization titer (NT50) of 4096, and mAb 7D7 partially neutralized CAdV-2 with a 50% NT50 of 64. Immunoprecipitation, Western blot and protein spectral analysis indicated that both neutralizing mAbs recognized the hexon protein (Hex) of CAdV-2. Through a 12-mer random peptide phage display and synthetic peptides analysis, we finely mapped the neutralizing epitopes to two 10-amino acid (aa) peptides within the CAdV Hex: 634RIKQRETPAL643 located on the surface region; and 736PESYKDRMYS745 located in the inner region of the expected 3D structure of trimeric Hex. Importantly, the two epitopes are highly conserved among all CAdV isolates by sequence alignment analysis. Thus, these results provide insights into the interaction between virus and mAbs at the aa level and may have potential applications in the development of novel therapeutic or epitope-based vaccines, antibody therapeutics and a diagnostic method suitable for the rapid detection of all CAdVs. Full article
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2020

Jump to: 2021

Article
Dissecting the NK Cell Population in Hematological Cancers Confirms the Presence of Tumor Cells and Their Impact on NK Population Function
Vaccines 2020, 8(4), 727; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines8040727 - 02 Dec 2020
Cited by 2 | Viewed by 1003
Abstract
The lymphocyte lineage natural killer (NK) cell is part of the innate immune system and protects against pathogens and tumor cells. NK cells are the main cell effectors of the monoclonal antibodies (mAbs) that mediates antibody-dependent cell cytotoxicity (ADCC). Hence, it is relevant [...] Read more.
The lymphocyte lineage natural killer (NK) cell is part of the innate immune system and protects against pathogens and tumor cells. NK cells are the main cell effectors of the monoclonal antibodies (mAbs) that mediates antibody-dependent cell cytotoxicity (ADCC). Hence, it is relevant to understand NK physiology and status to investigate the biological effect of mAbs in the clinic. NK cells are heterogeneous with multiple subsets that may have specific activity against different attacks. The presence of viral-sculpted NK cell populations has already been described, but the presence of cancer-sculpted NK cells remains unknown. Cancer induces a broad NK cell dysfunction, which has not been linked to a specific population. Here, we investigated the NK cell population by Uniform Manifold Approximation and Projection (UMAP) embed maps in Hodgkin lymphoma (HL) and acute myeloid leukemia (AML) patients at diagnosis and at least 30 days after treatment, which correlates with tumor cell clearance. We found that the NK lineage largely responded to the tumor by generating antitumor NK cells and renewing the population with a subset of immature NK cells. However, we failed to identify a specific “memory-like” subset with the NK cell markers used. Moreover, in patients in relapse, we found essentially the same NK populations as those found at diagnosis, suggesting that NK cells equally respond to the first or second tumor rise. Finally, we observed that previous cytomegalovirus (CMV) infection largely affects the tumor-associated changes in NK population, but the CMV-associated CD57+NKG2C+ NK cell population does not appear to play any role in tumor immunity. Full article
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: The potential of HLA-polyreactive IgG2a monoclonal antibodies (TFL-006 & TFL-007) mimicking the immune regulatory functions of therapeutic IVIg

Authors: Mepur H. Ravindranath M.Sc.Ph.D.1, Fatiha E. Hilali, Ph.D.2, Edward J Filippone M.D.3,
Affiliation: 1 Children’s Hospital, Los Angeles, CA 90027, USA 2 28 DB Dighoussi Zitoune Meknes, Morocco, 3 Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia PA 19145, USA
Abstract: Intravenous immunoglobulin (IVIg), is used for treatment of patients with antibody (Ab) deficiencies, neurological (dermatomyositis, GBS, inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, myasthenia gravis, and stiff person syndrome), hematological (immune cytopenias, parvovirus B19 associated red cell aplasia, hypogammaglobulinaemia and chronic lymphatic leukemia and post-bone marrow transplantation) disorders, immune thrombocytopenia, Kawasaki’s syndrome, intractable childhood epilepsy, autoimmune diseases (e.g. myasthenia gravis, systemic lupus erythematosus), idiopathic thrombocytopenic purpura, idiopathic neutropenia and aplastic anemia, atopic allergy with immunoglobulin G (IgG) subclass deficiency including bronchial asthma, bacterial (both Gram-positive and -negative), viral (herpes simplex, herpes zoster, EBV, polyoma, BK virus, cytomegalovirus, rotavirus and coronavirus) and fungal (Aspergillus) infections, multiple myeloma, and chronic B-cell lymphocytic leukemia. Furthermore, IVIg is used as a desensitization protocols for dialysis patients waiting for allografts and for treatment of Ab-mediated rejection post-transplantation. IVIg inhibits the differentiation, maturation, and functions of dentritic cells, suppression of T-cell activation, cell-mediated lympholysis, mixed-lymphocyte-culture reactivity, ADCC, B-cell differentiation, cytokines mediating GVHD and inflammatory responses, enhances suppressor-T-cell activity and stimulates the expansion and suppressive functions of T-regs (CD4, CD25, and Foxp3). This review elucidates as to how HLA class I polyreactive mAbs, TFL-006 & TFL-007 mAbs mimic the HLA-polyreactivity of IVIg as well as the immune functions of IVIg, namely (1) the suppression of antigen-specific activated T cells similar to IVIg but dose-wise superior to IVIg and (2) the more efficient suppression of anti-HLA Ab production by activated B cells by anti-HLA-E IgG2a mAbs over that of IVIg. (3) Both mAbs uniquely capable of expanding CD4+, CD25+ and Foxp3+T-regs, which by itself is known to suppress T and B cells involved in antibody production. Ultimately, the objective is to initiate further inquiry into the possibility of replacing IVIg with TFL-mAbs, the IVIg-mimetics.

Title: Dissecting the NK cell population in hematological cancers confirms the presence of tumor cells and their impact on NK population function

Authors: Martin Villalba Gonzalez et al
Affiliation: INSERM-UM1 U1040, Université de Montpellier 1, 34295 Montpellier Cedex 5, France
Abstract: The lymphocyte lineage natural killer (NK) cell is part of the innate immune system and protects against pathogens and tumor cells. NK are the main cell effectors of monoclonal antibodies (mAbs) generating antibody-dependent cell cytotoxicity (ADCC). Hence it is relevant to understand NK physiology and status to investigate the biological effect of mAbs in the clinic. NK cells are heterogeneous with multiple subsets that may have specific activity against different attacks. The presence of viral-sculpted NK cell populations has already been described, but the presence of cancer-sculpted NK remains unknown. Cancer induces a broad NK cell dysfunction, which has not been linked to a specific population. Here we investigated the NK cell population by Uniform Manifold Approximation and Projection (UMAP) embed maps in Hodgkin lymphoma (HL) and acute myeloid leukemia (AML) patients at diagnosis and at least 30 days after treatment, which correlates with tumor cell clearance. We found that the NK lineage largely responded to the tumor by generating antitumor NK cells and renewing the population with a subset of immature NK cells. However, we failed to identify a specific “memory-like” subset with the NK cell markers used. Moreover, in patients in relapse we found essentially the same NK populations that those found at diagnostic, suggesting that NK cells equally respond to the first or second tumor rise. Finally, we observed that previous CMV infection largely affects the tumor-associated changes in NK population, but the CMV-associated CD57+NKG2C+ NK cell population does not appear to play any role in tumor immunity.

Title: Monoclonal antibodies and engineered derivatives targeting surface and secreted proteins from staphylococci

Authors: Pietro Speziale
Affiliation: Pietro Speziale, Department of Molecular Medicine, Unit of Biochemistry, Viale Taramelli 3/b, 27100 Pavia, Italy
Abstract: Staphylococci (specifically Staphylococcus aureus and Staphylococcus epidermidis) cause diseases ranging from mild superficial skin infections and device-related infections to life threaning conditions, including pneumonia, arthritis endocarditis and sepsis. Following decades of antibiotic usage, staphylococci have developed antibiotic resistance. For this reason renewed interest has been generated in alternative therapeutic agents such as anti-staphylococcal vaccines and antibodies within the scientific community. Both staphylococcal species express a wide repertoire of surface and secreted virulence factors, which provide mechanisms (tissue adhesion, cell invasion, biofilm development) for both survival in diverse host niches and immune evasion. Thus the development of antibodies that block these specific antigens would offer protection against staphylococcal infections. In this review we report an update on efforts to develop anti-Staphylococci monoclonal antibodies (mAbs) and their engineered derivatives ( bifunctional mAbs, antibody-antibiotic conjugates; lysibodies) and the mechanism by which such antibodies can help in combatting infections. We also provide an overview of mAbs used in clinical trials and highlight their therapeutic potential in passive immunization approach.

Title: Antibody responses induced by single-dose immunization with Toxoplasma gondii VLPs vaccine

Authors: F.S. Quan et al
Affiliation: Kyung Hee University School of Medicine, Republic of Korea
Abstract: Single-dose vaccines would maximize vaccination coverage, improve patient convenience, and greatly reduce the costs of vaccination. In this study, virus-like particles (VLPs) expressing the inner membrane complex (IMC), rhoptry protein 18 (ROP18), and microneme protein 8 (MIC8) of Toxoplasma gondii were generated and a single dose of this VLP vaccine was used to intranasally immunize the mice with or without the synthetic oligodeoxynucleotides containing unmethylated CpG motifs (CpG-ODN). Adjuvanted VLPs immunization induced higher levels of parasite-specific IgG, IgG1, IgG2a, IgG2b, IgA, and IgM antibody responses in sera and intestines compared to unadjuvanted VLPs, with a significantly higher level of parasite-specific IgM antibody responses being detected at 1 week post-immunization in sera. Consistent with these results, vaccination with adjuvanted VLPs limited the inflammatory cytokine (TNF-α) response in the brain while enhancing the production of both Th1 and Th2-associated cytokines, thereby contributing to diminished brain cyst counts and lessened body weight loss following T. gondii ME49 challenge infection. These findings indicated that single-dose im munization-induced parasite-specific antibody isotypes may contribute to the protection against T. gondii infection.

Keyword: Toxoplasma gondii, virus-like particle, CpG-ODN, antibody response, cytokine

Title: Anti-CD47 monoclonal antibody: neoadjuvant therapy to treat triple-negative breast cancers

Authors: Yingnan Si1, Kai Chen1, Seulhee Kim1, Jia-Shiung Guan1, Lufang Zhou2,1, Xiaoguang “Margaret” Liu1,3#
Affiliation: 1Department of Biomedical Engineering, University of Alabama at Birmingham (UAB), 1825 University Blvd, Birmingham, AL 35294, USA; 2Department of Medicine, UAB, 703 19th Street South, Birmingham, AL 35294, USA; 3O’Neal Comprehensive Cancer Center, UAB, 1824 6th Avenue South, Birmingham, AL 35233, US.
Abstract: Triple-negative breast cancers (TNBCs) are highly metastatic and frequently recurrent post-surgery or chemotherapy. The cell surface glycoprotein CD47 plays important role in tumor invasion and metastasis promotion, but chemotherapy can boost CD47 expression in cancer cells. The goal of this study is to develop a monoclonal antibody (mAb)-based targeted therapy as neoadjuvant to treat TNBCs. Specifically, a new mAb that targets the 1st extracellular domain (19-141) of receptor CD47 with high surface binding and affinity was designed, developed using hybridoma technology, and produced from fed-batch process in stirred-tank bioreactor. The flow cytometry analysis and confocal imaging using cell lines (MDA-MB-468, MDA-MB-231, and 4T1) and In Vivo Imaging System (IVIS) imaging in orthotopic TNBC xenograft mouse models showed that the anti-CD47 mAb can effectively target TNBC cells and also deliver drugs. Moreover, the mAb can block CD47 signaling in TNBC and activate the tumoral immunity (macrophage and CD8+ T cells in tumor microenvironment), resulting in immunotherapy. High anti-cancer cytotoxicity of anti-CD47 mAb and mAb-drug (PBD and DM1) conjugate was observed in TNBC cell lines and drug resistant lines. Finally, we established a 4T1 xenograft immunocompetent BALB/c mice model, removed primary tumor with surgery, treated with chemotherapy, then followed with PBS (control), mAb and mAb-drug conjugate treatments. The anti-TNBC efficacy (tumor burden, metastasis, and survival) was improved by our anti-CD47-based targeted therapy. This study demonstrated that targeting CD47 with mAb has great potential to treat TNBCs as a neoadjuvant therapy.

Title: Future directions in research on monoclonal antibodies in the management of asthma

Authors: Grzegorz Kardas1, Piotr Damiański1, Piotr Kuna1, Michał Panek1, Maciej Kupczyk 1,*
Affiliation: Department of Internal Medicine, Asthma and Allergy, Medical University of Lodz, Łódź,      Poland
Abstract: Patients with moderate-to-severe asthma may now be treated using a variety of monoclonal antibodies that aim key inflammatory cytokines involved in disease pathogenesis. Existing clinical data on anti-IgE, anti-IL-5 and other immunological pathways shows much beneficial effects of these biological therapies in terms of reduction of exacerbation rates, improvement of lung functions, asthma control and patients' quality of life. However, several patients yet do not reach satisfactory clinical response with the antibodies available. Thus, many more, aiming different immunological pathways, are under evaluation.
In this review, the authors summarize recent data on existing and researched monoclonal antibodies in asthma. Recent advances show promising results in targeting TSLP (tezepelumab) or IL-33 (Itepekimab). Some of the researched monoclonal antibodies (eg. anti-IL-13 tralokinumab and lebrikizumab or anti-IL-17A secuinumab), although showing optimistic results in preliminary research, have been discontinued in asthma clinical research. Moreover, as patients with T2-low asthma were to date excluded from the therapeutic benefits of the available monoclonal antibodies, research in this area also progresses. Several antibodies – anti-IL-23 risankizumab or anti-eotaxin-1 bertilimumab – or oral drugs such as anti-IL1R anakinra are in development in this indication. In this article, we summarize the available pre-clinical and clinical data on new and emerging and indicate future directions in this area.

Title: Antigen recognition mechanism and optimization of a neutralizing human anti-hepatitis B virus preS1 monoclonal antibody

Authors: Jisu Hong, Young Jin Choi, Jiwoo Lee, Yoonjoo Choi, and Hyo Jeong Hong
Abstract: Hepatitis B virus (HBV) is a global health burden that causes acute or chronic infection. Persistent infection with HBV is a risk factor that develops cirrhosis and hepatocellular carcinoma. Therefore, generation of anti-HBV monoclonal antibodies (mAbs) that can effectively block the HBV infection is needed. We previously generated an anti-HBV preS1 monoclonal antibody (1A8) from a phage-displayed human synthetic Fab library. This antibody bound to major HBV genotypes (A-D) and neutralized HBV infection in an in vitro neutralization assay. In the present study, we determined the fine epitope of 1A8 and the antibody paratope through site-directed mutagenesis and structural analysis toward affinity maturation of 1A8. The alanine scanning mutagenesis of the preS1 region (aa 19-32) containing the HBV receptor-binding motif (aa 20-26) revealed that three residues (Leu22, Gly23, and Phe25) are essential in antibody binding, indicating that 1A8 antibody recognizes the fine epitope (aa 22-25) within the receptor-binding motif. The alanine scanning mutagenesis of the heavy chain (HCDRs) or light chain complementarity-determining regions (LCDRs) of 1A8 revealed that the four residues in each of the HCDR1, HCDR2, HCDR3, and LCDR3 are critical in antigen binding. Structural analysis of the antigen-antibody interaction by molecular modeling showed that the three residues in the fine epitope are in direct contact with the three residues in the HCDR2, HCDR3 and LCDR3. Of note, replacement of the HCDR2 residue by alanine resulted in an increase in the affinity by two-fold. Finally, a potential post-translational modification site in the heavy chain framework region of the affinity-improved variant was removed to construct a final candidate antibody (Hu1A8-2). Given that Hu1A8-2 antibody binds to the receptor-binding motif, this antibody may efficiently block the entry of most HBV genotypes and thus may be a good candidate for HBV immunoprophylaxis.

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