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Advances in Antibody Design and Antigenic Peptide Targeting

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (15 February 2019) | Viewed by 46896

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Prof. Dr. Gunnar Houen

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Guest Editor

Department of Neurology Rigshospitalet Glostrup, Valdemar Hansens vej 1-23, 2600 Glostrup, Denmark
Interests: antibodies; aptamers; peptides; peptide antibodies; recognition molecules; synthetic libraries
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Dr. Nicole Hartwig Trier

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Co-Guest Editor

Department of Autoimmunology and Biomarkers, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen S, Denmark
Interests: rheumatoid arthritis; anti-citrullinated protein antibodies; citrullinated epitopes; cyclic citrullinated peptides
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Dear Colleagues,

Peptides can be made synthetically in essentially unlimited amounts, with most post-translational modifications and with non-natural amino acid residues. This makes them valuable reagents for many purposes, e.g. T cell epitope mapping and (linear) B cell epitope mapping. However, they generally have very little defined structure unless they are heavily constrained by e.g. disulfide bridges, thus making them unsuitable as specific reagents for target recognition.

Antibodies are natural, large proteins with specific recognition properties and can undergo affinity maturation and class switching during immune responses (e.g., immunization) in vivo to achieve very high affinities and specific effector functions. Antibodies can be made in large amounts by recombinant technology and can be engineered in several ways to modify their properties, e.g., structure, immunogenicity and effector functions.

All antibodies recognize three-dimensional structures, but a distinction is usually made between epitopes containing residues far apart in the amino acid sequence and epitopes with residues close in the sequence. The latter are called linear epitopes and are mainly found in linker regions between protein domains, in non-structured parts of proteins and in N- and C-terminal sequences.

The use of synthetic peptides for production of antibodies (peptide antibodies) has been extremely rewarding in all areas of biology and biotechnology and continues to be of major importance. Peptide antibodies are particularly good at recognizing linear epitopes, post-translationally modified epitopes, and denatured proteins (e.g., Western immunoblotting). However, several goals remain to be achieved in relation to peptides and antibodies, including the design and synthesis of (constrained) peptides with specific recognition properties (peptibodies) and the use of peptides as therapeutic vaccines.

This issue of IJMS attempts to describe current knowledge about specially designed peptides and antibodies with a particular emphasis on sophisticated peptide antibodies.

Prof. Gunnar Houen
Dr. Nicole Trier
Guest Editors

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Keywords

antibodies
autoantibodies
diagnostics
epitope
epitope mapping
immunoassay
paratope
peptibodies
therapeutic antibodies

Published Papers (10 papers)

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Editorial

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2 pages, 144 KiB

Open AccessEditorial

Molecular Recognition and Advances in Antibody Design and Antigenic Peptide Targeting

by Gunnar Houen and Nicole Trier

Int. J. Mol. Sci. 2020, 21(4), 1405; https://doi.org/10.3390/ijms21041405 - 19 Feb 2020

Cited by 2 | Viewed by 1581

Abstract

Molecular recognition, the specific interaction between molecules by a combination of physical forces, has been a subject of scientific investigation for decades [...] Full article

(This article belongs to the Special Issue Advances in Antibody Design and Antigenic Peptide Targeting)

Research

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13 pages, 1871 KiB

Open AccessArticle

Fine Mapping of Glutamate Decarboxylase 65 Epitopes Reveals Dependency on Hydrophobic Amino Acids for Specific Interactions

by Niccolò Valdarnini, Bettina Holm, Paul Hansen, Paolo Rovero, Gunnar Houen and Nicole Trier

Int. J. Mol. Sci. 2019, 20(12), 2909; https://doi.org/10.3390/ijms20122909 - 14 Jun 2019

Cited by 7 | Viewed by 2808

Abstract

Characterization of multiple antibody epitopes has revealed the necessity of specific groups of amino acid residues for reactivity. This applies to the majority of antibody–antigen interactions, where especially charged and hydrophilic amino acids have been reported to be essential for antibody reactivity. This study describes thorough characterization of glutamic acid decarboxylase (GAD) 65 antigenic epitopes, an immunodominant autoantigen in type 1 diabetes (T1D). As linear epitopes are sparsely described for GAD65 in T1D, we aimed to identify and thoroughly characterize two GAD65 antibodies using immunoassays. A monoclonal antibody recognized an epitope in the N-terminal domain of GAD65, ⁸FWSFGSE¹⁴, whereas a polyclonal antibody recognized two continuous epitopes in the C-terminal domain, corresponding to amino acids ⁵¹⁴RTLED⁵¹⁸ and ⁵⁴⁹PLGDKVNF⁵⁵⁶. Hydrophobic amino acids were essential for antibody reactivity, which was verified by competitive inhibition assays. Moreover, the epitopes were located in flexible linker regions and turn structures. These findings confirm the versatile nature of antibody–antigen interactions and describe potential continuous epitopes related to T1D, which predominantly have been proposed to be of discontinuous nature. Full article

(This article belongs to the Special Issue Advances in Antibody Design and Antigenic Peptide Targeting)

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16 pages, 4848 KiB

Open AccessArticle

Identifying the Pathological Domain of Alpha- Synuclein as a Therapeutic for Parkinson’s Disease

by Ning Shen, Ge Song, Haiqiang Yang, Xiaoyang Lin, Breanna Brown, Yuzhu Hong, Jianfeng Cai and Chuanhai Cao

Int. J. Mol. Sci. 2019, 20(9), 2338; https://doi.org/10.3390/ijms20092338 - 11 May 2019

Cited by 15 | Viewed by 5351

Abstract

Alpha-synuclein is considered the major pathological protein associated with Parkinson’s disease, but there is still no effective immunotherapy which targets alpha-synuclein. In order to create a safer and more effective therapy against PD, we are targeting an epitope of alpha-synuclein rather than full-length alpha-synuclein. We have selected several antigenic domains (B-cell epitope) through antigenicity prediction, and also made several recombinant protein fragments from alpha-synuclein upon antigenicity prediction in an E. coli system. We then tested the function of each of the peptides and recombinant fragments in aggregation, their toxicity and antigenicity. We have discovered that the full-length recombinant (aa1–140) can aggregate into oligomers or even fibrils, and fragment aa15–65 can promote the aggregation of aa1–140. It is worth noting that it not only promotes whole protein aggregation, but also self-aggregates as seen by western blotting and silver staining assays. We have tested all candidates on primary neurons for their toxicity and discovered that aa15–65 is the most toxic domain compared to all other fragments. The antibody targeting this domain also showed both anti-aggregation activity and some therapeutic effect. Therefore, we believe that we have identified the most potent therapeutic domain of alpha synuclein as a therapeutic target. Full article

(This article belongs to the Special Issue Advances in Antibody Design and Antigenic Peptide Targeting)

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15 pages, 2250 KiB

Open AccessArticle

SpotLight Proteomics—A IgG-Enrichment Phenotype Profiling Approach with Clinical Implications

by Susanna L. Lundström, Tina Heyder, Emil Wiklundh, Bo Zhang, Anders Eklund, Johan Grunewald and Roman A. Zubarev

Int. J. Mol. Sci. 2019, 20(9), 2157; https://doi.org/10.3390/ijms20092157 - 01 May 2019

Cited by 8 | Viewed by 3132

Abstract

Sarcoidosis is a systemic interstitial lung disease of unknown aetiology. Less invasive diagnostics are needed to decipher disease pathology and to distinguish sub-phenotypes. Here we test if SpotLight proteomics, which combines de novo MS/MS sequencing of enriched IgG and co-extracted proteins with subsequent label-free quantification of new and known peptides, can differentiate controls and sarcoidosis phenotypes (Löfgrens and non-Löfgrens syndrome, LS and nonLS). Intra-individually matched IgG enriched from serum and bronchial lavage fluid (BALF) from controls (n = 12), LS (n = 11) and nonLS (n = 12) were investigated. High-resolution mass-spectrometry SpotLight proteomics and uni- and multivariate-statistical analyses were used for data processing. Major differences were particularly observed in control-BALF versus sarcoidosis-BALF. However, interestingly, information obtained from BALF profiles was still present (but less prominent) in matched serum profiles. By using information from orthogonal partial least squares discriminant analysis (OPLS-DA) differentiating 1) sarcoidosis-BALF and control-BALF and 2) LS-BALF vs. nonLS-BALF, control-serum and sarcoidosis-serum (p = 0.0007) as well as LS-serum and nonLS-serum (p = 0.006) could be distinguished. Noteworthy, many factors prominent in identifying controls and patients were those associated with Fc-regulation, but also features from the IgG-Fab region and novel peptide variants. Differences between phenotypes were mostly IgG-specificity related. The results support the analytical utility of SpotLight proteomics which prospectively have potential to differentiate closely related phenotypes from a simple blood test. Full article

(This article belongs to the Special Issue Advances in Antibody Design and Antigenic Peptide Targeting)

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13 pages, 1956 KiB

Open AccessArticle

Computational Analysis of Dengue Virus Envelope Protein (E) Reveals an Epitope with Flavivirus Immunodiagnostic Potential in Peptide Microarrays

by Greta Bergamaschi, Enrico M. A. Fassi, Alessandro Romanato, Ilda D'Annessa, Maria Teresa Odinolfi, Dario Brambilla, Francesco Damin, Marcella Chiari, Alessandro Gori, Giorgio Colombo and Marina Cretich

Int. J. Mol. Sci. 2019, 20(8), 1921; https://doi.org/10.3390/ijms20081921 - 18 Apr 2019

Cited by 26 | Viewed by 5094

Abstract

The mosquito-borne viral disease caused by the Dengue virus is an expanding global threat. Diagnosis in low-resource-settings and epidemiological surveillance urgently requires new immunoprobes for serological tests. Structure-based epitope prediction is an efficient method to design diagnostic peptidic probes able to reveal specific antibodies elicited in response to infections in patients’ sera. In this study, we focused on the Dengue viral envelope protein (E); computational analyses ranging from extensive Molecular Dynamics (MD) simulations and energy-decomposition-based prediction of potentially immunoreactive regions identified putative epitope sequences. Interestingly, one such epitope showed internal dynamic and energetic properties markedly different from those of other predicted sequences. The epitope was thus synthesized as a linear peptide, modified for chemoselective immobilization on microarrays and used in a serological assay to discriminate Dengue-infected individuals from healthy controls. The synthetic epitope probe showed a diagnostic performance comparable to that of the full antigen in terms of specificity and sensitivity. Given the high level of sequence identity among different flaviviruses, the epitope was immune-reactive towards Zika-infected sera as well. The results are discussed in the context of the quest for new possible structure-dynamics-based rules for the prediction of the immunoreactivity of selected antigenic regions with potential pan-flavivirus immunodiagnostic capacity. Full article

(This article belongs to the Special Issue Advances in Antibody Design and Antigenic Peptide Targeting)

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11 pages, 1483 KiB

Open AccessArticle

CD20-Mimotope Peptides: A Model to Define the Molecular Basis of Epitope Spreading

by Elvira Favoino, Marcella Prete, Giacomo Catacchio, Giuseppina Conteduca and Federico Perosa

Int. J. Mol. Sci. 2019, 20(8), 1920; https://doi.org/10.3390/ijms20081920 - 18 Apr 2019

Cited by 9 | Viewed by 3468

Abstract

Antigen-mimicking peptide (mimotope)-based vaccines are one of the most promising forms of active-immunotherapy. The main drawback of this approach is that it induces antibodies that react poorly with the nominal antigen. The aim of this study was to investigate the molecular basis underlying the weak antibody response induced against the naïve protein after peptide vaccination. For this purpose, we analyzed the fine specificity of monoclonal antibodies (mAb) elicited with a 13-mer linear peptide, complementary to theantigen-combining site of the anti-CD20 mAb, Rituximab, in BALB/c mice. Anti-peptide mAb competed with Rituximab for peptide binding. Even so, they recognized a different antigenic motif from the one recognized by Rituximab. This explains their lack of reactivity with membrane (naïve) CD20. These data indicate that even on a short peptide the immunogenic and antigenic motifs may be different. These findings highlight an additional mechanism for epitope spreading and should be taken into account when designing peptides for vaccine purposes. Full article

(This article belongs to the Special Issue Advances in Antibody Design and Antigenic Peptide Targeting)

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17 pages, 6761 KiB

Open AccessArticle

Optimization of Sequence, Display, and Mode of Operation of IgG-Binding Peptide Ligands to Develop Robust, High-Capacity Affinity Adsorbents That Afford High IgG Product Quality

by Tuhidul Islam, Amith D. Naik, Yasuhiro Hashimoto, Stefano Menegatti and Ruben G. Carbonell

Int. J. Mol. Sci. 2019, 20(1), 161; https://doi.org/10.3390/ijms20010161 - 04 Jan 2019

Cited by 18 | Viewed by 5705

Abstract

This work presents the use of peptide ligand HWRGWV and its cognate sequences to develop affinity adsorbents that compete with Protein A in terms of binding capacity and quality of the eluted product. First, the peptide ligand was conjugated to crosslinked agarose resins (WorkBeads) at different densities and using different spacer arms. The optimization of ligand density and display resulted in values of static and dynamic binding capacity of 85 mg/mL and 65 mg/mL, respectively. A selected peptide-WorkBeads adsorbent was utilized for purifying Mabs from Chinese Hamster Ovary (CHO) cell culture supernatants. The peptide-WorkBeads adsorbent was found able to withstand sanitization with strong alkaline solutions (0.5 M NaOH). The purity of the eluted product was consistently higher than 95%, with logarithmic removal value (LRV) of 1.5 for host cell proteins (HCPs) and 4.0 for DNA. HCP clearance was significantly improved by adding a post-load washing step with either 0.1 M Tris HCl pH 9 or 1 M NaCl. The cognate peptide of HWRGWV, constructed by replacing arginine (R) with citrulline, further increased the HCP LRV to 2.15. The peptide-based adsorbent also showed a remarkable performance in terms of removal of Mab aggregates; unlike Protein A, in fact, HWRGWV was found to bind only monomeric IgG. Collectively, these results demonstrate the potential of peptide-based adsorbents as alternative to Protein A for the purification of therapeutic antibodies. Full article

(This article belongs to the Special Issue Advances in Antibody Design and Antigenic Peptide Targeting)

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Review

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22 pages, 1078 KiB

Open AccessReview

Peptides, Antibodies, Peptide Antibodies and More

by Nicole Trier, Paul Hansen and Gunnar Houen

Int. J. Mol. Sci. 2019, 20(24), 6289; https://doi.org/10.3390/ijms20246289 - 13 Dec 2019

Cited by 70 | Viewed by 6253

Abstract

The applications of peptides and antibodies to multiple targets have emerged as powerful tools in research, diagnostics, vaccine development, and therapeutics. Antibodies are unique since they, in theory, can be directed to any desired target, which illustrates their versatile nature and broad spectrum of use as illustrated by numerous applications of peptide antibodies. In recent years, due to the inherent limitations such as size and physical properties of antibodies, it has been attempted to generate new molecular compounds with equally high specificity and affinity, albeit with relatively low success. Based on this, peptides, antibodies, and peptide antibodies have established their importance and remain crucial reagents in molecular biology. Full article

(This article belongs to the Special Issue Advances in Antibody Design and Antigenic Peptide Targeting)

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32 pages, 1073 KiB

Open AccessReview

Cognizance of Molecular Methods for the Generation of Mutagenic Phage Display Antibody Libraries for Affinity Maturation

by Chia Chiu Lim, Yee Siew Choong and Theam Soon Lim

Int. J. Mol. Sci. 2019, 20(8), 1861; https://doi.org/10.3390/ijms20081861 - 15 Apr 2019

Cited by 27 | Viewed by 8149

Abstract

Antibodies leverage on their unique architecture to bind with an array of antigens. The strength of interaction has a direct relation to the affinity of the antibodies towards the antigen. In vivo affinity maturation is performed through multiple rounds of somatic hypermutation and selection in the germinal centre. This unique process involves intricate sequence rearrangements at the gene level via molecular mechanisms. The emergence of in vitro display technologies, mainly phage display and recombinant DNA technology, has helped revolutionize the way antibody improvements are being carried out in the laboratory. The adaptation of molecular approaches in vitro to replicate the in vivo processes has allowed for improvements in the way recombinant antibodies are designed and tuned. Combinatorial libraries, consisting of a myriad of possible antibodies, are capable of replicating the diversity of the natural human antibody repertoire. The isolation of target-specific antibodies with specific affinity characteristics can also be accomplished through modification of stringent protocols. Despite the ability to screen and select for high-affinity binders, some ‘fine tuning’ may be required to enhance antibody binding in terms of its affinity. This review will provide a brief account of phage display technology used for antibody generation followed by a summary of different combinatorial library characteristics. The review will focus on available strategies, which include molecular approaches, next generation sequencing, and in silico approaches used for antibody affinity maturation in both therapeutic and diagnostic applications. Full article

(This article belongs to the Special Issue Advances in Antibody Design and Antigenic Peptide Targeting)

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18 pages, 682 KiB

Open AccessReview

Advances in Antigenic Peptide-Based Vaccine and Neutralizing Antibodies against Viruses Causing Hand, Foot, and Mouth Disease

by Mohd Ishtiaq Anasir and Chit Laa Poh

Int. J. Mol. Sci. 2019, 20(6), 1256; https://doi.org/10.3390/ijms20061256 - 13 Mar 2019

Cited by 28 | Viewed by 4389

Abstract

Hand, foot, and mouth disease (HFMD) commonly produces herpangina, but fatal neurological complications have been observed in children. Enterovirus 71 (EV-A71) and Coxsackievirus 16 (CV-A16) are the predominant viruses causing HFMD worldwide. With rising concern about HFMD outbreaks, there is a need for an effective vaccine against EV-A71 and CV-A16. Although an inactivated vaccine has been developed against EV-A71 in China, the inability of the inactivated vaccine to confer protection against CV-A16 infection and other HFMD etiological agents, such as CV-A6 and CV-A10, necessitates the exploration of other vaccine platforms. Thus, the antigenic peptide-based vaccines are promising platforms to develop safe and efficacious multivalent vaccines, while the monoclonal antibodies are viable therapeutic and prophylactic agents against HFMD etiological agents. This article reviews the available information related to the antigenic peptides of the etiological agents of HFMD and their neutralizing antibodies that can provide a basis for the design of future therapies against HFMD etiological agents. Full article

(This article belongs to the Special Issue Advances in Antibody Design and Antigenic Peptide Targeting)

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