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Single-Domain Antibodies: Biology, Engineering and Emerging Applications

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889454327 Year: Pages: 338 DOI: 10.3389/978-2-88945-432-7 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2018-11-16 17:17:57
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Single-domain antibodies (sdAbs) represent the minimal antigen binding-competent form of the immunoglobulin domain and have unique properties and applications. SdAbs are naturally produced as the variable domains of the heavy chain-only antibodies of camelid ruminants and cartilaginous fishes, but can also be engineered synthetically from autonomous human or mouse VH or VL domains. The scope of this research topic and associated e-book covers current understanding and new developments in (i) the biology, immunology and immunogenetics of sdAbs in camelids and cartilaginous fishes, (ii) strategies for sdAb discovery, (iii) protein engineering approaches to increase the solubility, stability and antigen-binding affinity of sdAbs and (iv) specialized applications of sdAbs in areas such diagnostics, imaging and therapeutics.

Vaccines, Immunotherapy and New Antifungal Therapy Against Fungi: Updates in the New Frontier

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889453276 Year: Pages: 183 DOI: 10.3389/978-2-88945-327-6 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Microbiology
Added to DOAB on : 2018-02-27 16:16:45
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Invasive fungal diseases have increased many fold over the past 50 years. Current treatment regimens typically require prolonged administration of antifungal medications that can have significant toxicity. Moreover, our present potent antifungal armamentarium fails to eradicate fungal pathogens from certain compromised hosts. Additionally, invasive fungal diseases continue to have unacceptably high mortality rates. A growing body of work has focused on the utility of vaccines and/or immunotherapy as a powerful tool in combating mycoses, either for the active treatment, as an adjuvant, or in the prevention of specific fungal pathogens. Also, it is growing the interest over new drugs development as second choice for treatment when traditional chemotherapy fail. This Research Topic will detail the exciting progress in developing vaccines, immunotherapy and new drugs for fungi.

Influenza Virus Vaccines and Immunotherapies

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889198115 Year: Pages: 185 DOI: 10.3389/978-2-88919-811-5 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2016-01-19 14:05:46
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Influenza virus infections lead to thousands of deaths worldwide annually and billions of dollars economic burden. Despite continuing advances in our understanding of the immune evasion mechanism, the disease remains one of the foremost threat for human being. Traditional vaccines (attenuated and inactivated) mainly provide protection by inducing virus neutralizing antibodies, targeting ever changing surface antigens: Haemagultinin (HA) and Neuraminidase (NA). Due to genetic shift and immune selection pressure, prevalence of circulating influenza virus subtypes changes every year. Therefore, mismatch between circulating strain and vaccine strain can critically affect the success rate of these conventional flu vaccines, and requires continuous monitoring of circulating influenza virus subtypes and change in the vaccine formulations accordingly. The collective limitations of existing flu vaccines urgently call for the development of a novel universal vaccines that might provide the required protective immunity to a range of influenza virus subtypes. New approaches are being investigated mainly targeting conserved regions of flu proteins. Some of these approaches include universally conserved epitopes of HA, nucleoprotein (NP), capsid protein (M1) and ion channel protein (M2) that induced strong immune responses in animal models. Some attention and progress appears to be focused on vaccines based on the M2 ectodomain (M2e) employing a variety of constructs, adjuvants and delivery systems, including M2e-hepatitis B core antigen, flagellin constructs, and virus-like particles (VLP). Animal studies with these M2e candidate vaccines demonstrated that these vaccine candidates can prevent severe illness and death but not infection, which may pose difficulties in both the evaluation of clinical efficacy and approval by the regulatory authorities. VLP vaccines appear to be promising, but still are mostly limited to animal studies. The discovery and development of new and improved vaccines have been greatly facilitated by the application of new technologies. The use of nucleic acid-based vaccines, to combine the benefits of in-situ expression of antigens with the safety of inactivated and subunit vaccines, has been a key advancement. Upon their discovery more than 20 years ago, nucleic acid vaccines promised to be a safe and effective mean to mimic immunization with a live organism vaccine, particularly for induction of T cell immunity. In addition, the manufacturing of nucleic acid-based vaccines offered the potential to be relatively simple, inexpensive and generic. Reverse Vaccinology and in-silico designing of vaccines are very innovative approaches and being considered as future of vaccines. Furthermore, various immuno-therapeutic agents also being developed to treat and minimize immuno-pathological damage in patients suffering from life threatening complications. For the treatment of such pathological conditions, various novel approaches such as administration of immune suppressive cytokines, blocking co-stimulatory signals or activating co-inhibitory signal of T cell activation, are being tested both in lab and clinics. The Research Topic on influenza virus vaccine and therapeutics will give an insight in to the current status and future scope of these new innovative approaches and technologies. Moreover, these new methods will also serve as a reference tool for the development of future vaccines against several other pathogens.

A living history of immunology

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889196982 Year: Pages: 62 DOI: 10.3389/978-2-88919-698-2 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2016-08-16 10:34:25
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In the highly competitive world of biomedical science, often the rush to publish and to be recognized as "first" with a new discovery, concept or method, is lost in the hurly-burly of the moment, as "the maddening crowd" moves on to the next "new thing". One of the great things about immunology today is that it has only become mature as a science within the last half-century, and especially within the past 35 years as a consequence of the revolution of molecular immunology, which has taken place only since 1980. Consequently, most of those who have contributed to our new understanding of how the immune system functions are still alive and well, and still contributing. Thus, "A Living History of Immunology" collates many stories from the investigators who actually performed the experiments that have established the frontiers of immunology. Accordingly, this volume combats "revisionist science", by those who want to alter history by telling the stories a different way than actually happened. In this regard, one of the good things about science vs. other disciplines is that we have the written record of what was done, when it was done and by whom. Even so, we do not have the complete story or narrative of how and why experiments were done, and what made the differences that led to success. This volume captures and chronicles some of these stories from the past fifty years in immunology.

Antibody Repertoire and Graft Outcome Following Solid Organ Transplantation

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889452415 Year: Pages: 176 DOI: 10.3389/978-2-88945-241-5 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2017-10-13 14:57:01
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The first real major breakthrough that laid the basis of HLA antibody detection in the field of solid organ transplantation, came with the introduction of the complement dependent cytotoxicity (CDC) test in 1964 by Terasaki and McClelland. Since then, methods for antibody detection have evolved remarkably from conventional cell-based assays to the current advanced solid phase systems on the Luminex platform, with increasing degree of sensitivity and specificity. The latter have been indispensable for more accurate identification of donor specific HLA antibodies in broadly reactive allo antisera, and to guide donor selection and kidney paired exchange programs through virtual crossmatching, in addition to serving as excellent tools for initiating pre-transplant desensitization and post- transplant antibody monitoring. Consensus is evolving on the optimal routine employment of these methods in donor selection strategies along with an understanding of the clinical relevance of antibodies detected by each of them. The immunoassays based on the Luminex platform and flow cytometric beads are however unable to discriminate complement fixing from non-complement fixing HLA antibodies. This is important because the former are considered clinically more pertinent in the peri-transplant period. The C1q assay which is a modification of the solid phase assay based on Luminex single antigen beads, which can be used effectively to monitor high dose IVIG desensitization is essentially a surrogate complement fixing assay, retaining the exquisite sensitivity and specificity of the Luminex platform. Currently, information obtained from these assays is preliminary and much needs to be done to standardize technologies and set a consensus ‘MFI cut off’ for antibody positivity. Besides the overriding influence of anti-HLA antibodies on overall solid organ graft survival, immune response to non-HLA antigens has become a topic of substantial interest in recent years. An ever expanding list of non-HLA antigens has been implicated in graft rejection for various organs, of which the most noted are the Major Histocompatibility Complex class I chain-related molecule A (MICA), Vimentin, Myosin, Angiotensin II type 1 receptor (AT1R), Tubulin and Collagen. MICA is one of the most polymorphic and extensively studied non-HLA antigenic targets especially in renal transplantation. Although there are clear indications of MICA antibodies being associated with adverse graft outcome, to date a definitive consensus on this relationship has not been agreed. Because MICA molecules are not expressed constitutively on immunocompetent cells such as T and B lymphocytes, it is of utmost importance to address the impact of MICA donor specific antibodies (DSA) as compared to those that are non- donor specific (NDSA) on graft outcome. The soluble isoform of MICA molecule (sMICA) that is derived from the proteolytic shedding of membrane bound molecules has the potential to engage the NK-cell activating receptor NKG2D and down-regulate its expression. Consequent to the interaction of NKG2D by sMICA, the receptor ligand complex is endocytosed and degraded and thus suppresses NKG2D mediated lysis of the target by NK cells. Thus interaction between NKG2D and sMICA leads to expansion of immunosuppressive/anergic T cells thereby resulting in suppression of NKG2D mediated host innate immunity. These concept support the possible involvement of an immunosuppressive role for sMICA during allotransplantation as shown recently for heart transplantation. This research topic focuses on the clinical utility of investigating the complete antibody repertoire in solid organ transplantation.

The Evolution and Development of the Antibody Repertoire

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889195497 Year: Pages: 122 DOI: 10.3389/978-2-88919-549-7 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2016-01-19 14:05:46
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Although at first glance mechanisms used to create the variable domains of immunoglobulin appear to be designed to generate diversity at random, closer inspection reveals striking evolutionary constraints on the sequence and structure of these antigen receptors, suggesting that natural selection is operating to create a repertoire that anticipates or is biased towards recognition of specific antigenic properties. This Research Topics issue will be devoted to an examination of the evolution of antigen receptor sequence at the germline level, an evaluation of the repertoire in B cells from fish, pigs and human, an introduction into bioinformatics approaches to the evaluation and analysis of the repertoire as ascertained by high throughput sequencing, and a discussion of how study of the normal repertoire informs the construction or selection of in vitro antibodies for applied purposes.

Antibody Fc Engineering: Towards Better Therapeutics

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889456789 Year: Pages: 118 DOI: 10.3389/978-2-88945-678-9 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2019-01-23 14:53:43
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Monoclonal antibodies and Fc-fusion proteins used clinically are Fc-based therapeutics that grow fastest in the pharmaceutical industry. Since they both contain an Fc fragment, engineering of Fc fragments could be a platform for improving Fc-based drug efficacy. Fc engineering includes various aspects: stabilization of Fc; regulation of effector functions including antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity; extension of serum half-life by modification of neonatal Fc receptor (FcRn) binding; monomerization or heterodimerization of Fc for design of new Fc formats. Currently, many new methods are being used in Fc engineering. Compared to traditional methods such as site mutagenesis on certain positions by amino acid replacement, new methods such as display-based technology can confer high throughput screening and obtain optimized variants relatively quickly, accelerating the drug development process. With the new methods, many new Fc variants were identified. On this Research Topic we are going to review the progress in current Fc engineering including the new engineering methods and the Fc variants or constructs they have produced, and the potential of these new Fcs in clinical use.

Is the Recent Burst of Therapeutic Anti-Tumor Antibodies the Tip of an Iceberg?

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889454624 Year: Pages: 305 DOI: 10.3389/978-2-88945-462-4 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2018-11-16 17:17:57
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The high effectiveness of antibodies as anti-tumor therapeutic agents has led to a burst of research aiming to increase their therapeutic applications by the use of antibodies against new targets, new antibody formats or new combinations. In this e-book we present relevant research depicting the current efforts in the field.

Immune responses to AAV vectors, from bench to bedside

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889195008 Year: Pages: 95 DOI: 10.3389/978-2-88919-500-8 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2015-12-03 13:02:24
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The recent wave of clinical studies demonstrating long-term therapeutic efficacy highlights the enormous potential of gene therapy as an approach to the treatment of inherited disorders and cancer. While in recent years lentiviral vectors have dominated the field of ex vivo gene therapy in man, adeno-associated virus (AAV) vectors have become the platform of choice for the in vivo gene delivery, both local and systemic.Despite the achievements in the clinic however, a number of hurdles remain to be overcome in gene therapy, these include availability of scalable vector production systems, potential issues associated with insertional mutagenesis, and concerns related to immunogenicity of gene therapeutics. For AAV vectors, clinical trials showed that immunity directed against the vector could either prevent transduction of a target tissue or limit the duration of therapeutic efficacy. Initial observations in the context of a gene therapy trial for hemophilia spurred over a decade efforts by gene therapists and immunologists to understand the mechanism and identify factors that contribute to AAV’s immunogenicity, including the prevalence of B cell and T cell immunity to wild type AAV in humans and the interaction of AAV vectors with the innate and adaptive immune system. Despite a number of important contributions in particular in the more recent past, our knowledge on the immunology of gene transfer is still rudimental; this is partly due to the fact that the basic understanding of the complex balance between tolerance and immunity to an antigen, key aspect of gene transfer with AAV, keeps evolving rapidly. However, continuing work towards a better definition of the interaction of viral vectors with the immune system has led to significant advances in the knowledge of the factors influencing the outcome of gene transfer, such as the vector dose, the immune privilege of certain tissues, and the induction of tolerance to an antigen. A better understanding of the structure-function relationship of the viral capsid has boosted the development of novel immune-escape vector variants. In addition, novel immunomodulatory strategies were established to prevent or reduce anti-capsid immunity have been developed and are being tested in preclinical models and in clinical trials. Together, these advances are bringing us closer to the goal of achieving safe and sustained therapeutic gene transfer in humans. In this research topic, a collection of Original Research and Review Articles highlights critical aspects of the interaction between gene AAV vectors and the immune system, discussing how these interactions can be either detrimental or constitute an advantage, depending on the context of gene transfer, and providing tools and resources to better understand the issue of immunogenicity of AAV vectors in gene transfer.

Paradigm changes are required in HIV vaccine research

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889197279 Year: Pages: 74 DOI: 10.3389/978-2-88919-727-9 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2016-04-07 11:22:02
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In his 1962 book "The Structure of Scientific Revolutions", Thomas Kuhn famously argued that researchers in every field of scientific enquiry always operate under a set of presuppositions known as paradigms that are rarely explicitly stated. In the field of HIV vaccine research, several prevailing paradigms led scientists for many years to pursue unfruitful lines of investigations that impeded significant progress. The uncritical acceptance of reigning paradigms makes scientists reluctant to abandon their mistaken assumptions even when they obtain results that are not consistent with the paradigms. The following five paradigms which disregard the degeneracy of the immune system were particularly harmful. 1) There is a primary and intrinsic epitope specific for each B cell receptor and for the corresponding monoclonal antibody.In reality, there is no single, intrinsic or "real" epitope for any antibody but only a diverse group of potential ligands. 2) Reactions with monoclonal antibodies are more specific than the combined reactivity of polyclonal antibodies. In reality, a polyclonal antiserum has greater specificity for a multiepitopic protein because different antibodies in the antiserum recognize separate epitopes on the same protein, giving rise to an additive specificity effect. By focusing vaccine design on single epitope-Mab pairs, the beneficial neutralizing synergy that occurs with polyclonal antibody responses is overlooked. 3) The HIV epitope identified by solving the crystallographic structure of a broadly neutralizing Mab – HIV Env complex should be able, when used as immunogen, to elicit antibodies endowed with the same neutralizing capacity as the Mab. Since every anti HIV bnMab is polyspecific, the single epitope identified in the complex is not necessarily the one that elicited the bnMab. Since hypermutated Mabs used in crystallographic studies differ from their germline-like receptor version present before somatic hypermutation, the identified epitope will not be an effective vaccine immunogen. 4) Effective vaccine immunogenicity can be predicted from the antigenic binding capacity of viral epitopes. Most fragments of a viral antigen can induce antibodies that react with the immunogen, but this is irrelevant for vaccination since these antibodies rarely recognize the cognate, intact antigen and even more rarely neutralize the infectivity of the viral pathogen that harbors the antigen. 5) The rational design of vaccine immunogens using reverse vaccinology is superior to the trial-and-error screening of vaccine candidates able to induce protective immunity. One epitope can be designed to increase its structural complementarity to one particular bnMab, but such antigen design is only masquerading as immunogen design because it is assumed that antigenic reactivity necessarily entails the immunogenic capacity to elicit neutralizing antibodies. When HIV Env epitopes, engineered to react with a bnMab are used to select from human donors rare memory B cells secreting bnAbs, this represents antigen design and not immunogen design. The aim of this Research Topic is to replace previous misleading paradigms by novel ones that better fit our current understanding of immunological specificity and will help HIV vaccine development.

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