scholarly journals Regulatory approved monoclonal antibodies contain framework mutations predicted from human antibody repertoires

2021 ◽  
Author(s):  
Brian M Petersen ◽  
Sophia A Ulmer ◽  
Emily R Rhodes ◽  
Matias F Gutierrez Gonzalez ◽  
Brandon J Dekosky ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
High Frequency ◽  
In Silico ◽  
Sequence Data ◽  
Antibody Repertoire ◽  
Human Antibody ◽  
Therapeutic Antibodies ◽  
T Cell Epitopes ◽  
Antibody Repertoires ◽  
Dynamics Simulations

Monoclonal antibodies (mAbs) are an important class of therapeutics used to treat cancer, inflammation, and infectious diseases. Identifying highly developable mAb sequences in silico could greatly reduce the time and cost required for therapeutic mAb development. Here, we present position-specific scoring matrices (PSSMs) for antibody framework mutations developed using natural human antibody repertoire sequences. Our analysis shows that natural human antibody repertoire-based PSSMs are consistent across individuals and demonstrate high correlations between related germlines. We show that mutations in existing therapeutic antibodies can be accurately predicted solely from natural human antibody sequence data. mAbs developed using humanized mice had more human-like FR mutations than mAbs originally developed by hybridoma technology. A quantitative assessment of entire framework regions of therapeutic antibodies revealed that there may be potential for improving the properties of existing therapeutic antibodies by incorporating additional mutations of high frequency in natural human antibody repertoires. In addition, high frequency mutations in natural human antibody repertoires were predicted in silico to reduce immunogenicity in therapeutic mAbs due to the removal of T cell epitopes. Several therapeutic mAbs were identified to have common, universally high-scoring framework mutations, and molecular dynamics simulations revealed the mechanistic basis for the evolutionary selection of these mutations. Our results suggest that natural human antibody repertoires may be useful as predictive tools to guide mAb development in the future.

scholarly journals Regulatory Approved Monoclonal Antibodies Contain Framework Mutations Predicted From Human Antibody Repertoires

2021 ◽  
Vol 12 ◽  
Author(s):  
Brian M. Petersen ◽  
Sophia A. Ulmer ◽  
Emily R. Rhodes ◽  
Matias F. Gutierrez-Gonzalez ◽  
Brandon J. Dekosky ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
High Frequency ◽  
In Silico ◽  
Sequence Data ◽  
Antibody Repertoire ◽  
Human Antibody ◽  
Therapeutic Antibodies ◽  
T Cell Epitopes ◽  
Antibody Repertoires ◽  
Dynamics Simulations

Monoclonal antibodies (mAbs) are an important class of therapeutics used to treat cancer, inflammation, and infectious diseases. Identifying highly developable mAb sequences in silico could greatly reduce the time and cost required for therapeutic mAb development. Here, we present position-specific scoring matrices (PSSMs) for antibody framework mutations developed using baseline human antibody repertoire sequences. Our analysis shows that human antibody repertoire-based PSSMs are consistent across individuals and demonstrate high correlations between related germlines. We show that mutations in existing therapeutic antibodies can be accurately predicted solely from baseline human antibody sequence data. We find that mAbs developed using humanized mice had more human-like FR mutations than mAbs originally developed by hybridoma technology. A quantitative assessment of entire framework regions of therapeutic antibodies revealed that there may be potential for improving the properties of existing therapeutic antibodies by incorporating additional mutations of high frequency in baseline human antibody repertoires. In addition, high frequency mutations in baseline human antibody repertoires were predicted in silico to reduce immunogenicity in therapeutic mAbs due to the removal of T cell epitopes. Several therapeutic mAbs were identified to have common, universally high-scoring framework mutations, and molecular dynamics simulations revealed the mechanistic basis for the evolutionary selection of these mutations. Our results suggest that baseline human antibody repertoires may be useful as predictive tools to guide mAb development in the future.

scholarly journals Signatures of selection in the human antibody repertoire: Selective sweeps, competing subclones, and neutral drift

2019 ◽  
Vol 116 (4) ◽  
pp. 1261-1266 ◽  
Author(s):  
Felix Horns ◽  
Christopher Vollmers ◽  
Cornelia L. Dekker ◽  
Stephen R. Quake
Keyword(s):  
B Cell ◽  
Binding Affinity ◽  
Antibody Repertoire ◽  
Human Antibody ◽  
Selective Sweeps ◽  
Human Immune System ◽  
Evolutionary Processes ◽  
Neutral Drift ◽  
Cell Lineages ◽  
Antibody Repertoires

Antibodies are created and refined by somatic evolution in B cell populations, which endows the human immune system with the ability to recognize and eliminate diverse pathogens. However, the evolutionary processes that sculpt antibody repertoires remain poorly understood. Here, using an unbiased repertoire-scale approach, we show that the population genetic signatures of evolution are evident in human B cell lineages and reveal how antibodies evolve somatically. We measured the dynamics and genetic diversity of B cell responses in five adults longitudinally before and after influenza vaccination using high-throughput antibody repertoire sequencing. We identified vaccine-responsive B cell lineages that carry signatures of selective sweeps driven by positive selection, and discovered that they often display evidence for selective sweeps favoring multiple subclones. We also found persistent B cell lineages that exhibit stable population dynamics and carry signatures of neutral drift. By exploiting the relationship between B cell fitness and antibody binding affinity, we demonstrate the potential for using phylogenetic approaches to identify antibodies with high binding affinity. This quantitative characterization reveals that antibody repertoires are shaped by an unexpectedly broad spectrum of evolutionary processes and shows how signatures of evolutionary history can be harnessed for antibody discovery and engineering.

scholarly journals Native Human Monoclonal Antibodies with Potent Cross-Lineage Neutralization of Influenza B Viruses

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Adam Vigil ◽  
Angeles Estélles ◽  
Lawrence M. Kauvar ◽  
Scott K. Johnson ◽  
Ralph A. Tripp ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Germ Line ◽  
Transient Transfection ◽  
Influenza Viruses ◽  
Influenza B ◽  
Antibody Repertoire ◽  
Human Antibody ◽  
Human Monoclonal Antibodies ◽  
Head Region ◽  
Multiple Strains

ABSTRACTAlthough antibodies that effectively neutralize a broad set of influenza viruses exist in the human antibody repertoire, they are rare. We used a single-cell screening technology to identify rare monoclonal antibodies (MAbs) that recognized a broad set of influenza B viruses (IBV). The screen yielded 23 MAbs with diverse germ line origins that recognized hemagglutinins (HAs) derived from influenza strains of both the Yamagata and Victoria lineages of IBV. Of the 23 MAbs, 3 exhibited low expression in a transient-transfection system, 4 were neutralizers that bound to the HA head region, 11 were stalk-binding nonneutralizers, and 5 were stalk-binding neutralizers, with 4 of these 5 having unique antibody sequences. Of these four unique stalk-binding neutralizing MAbs, all were broadly reactive and neutralizing against a panel of multiple strains spanning both IBV lineages as well as highly effective in treating lethal IBV infections in mice at both 24 and 72 h postinfection. The MAbs in this group were thermostable and bound different epitopes in the highly conserved HA stalk region. These characteristics suggest that these MAbs are suitable for consideration as candidates for clinical studies to address their effectiveness in the treatment of IBV-infected patients.

scholarly journals Large-scale sequence and structural comparisons of human naive and antigen-experienced antibody repertoires

2016 ◽  
Vol 113 (19) ◽  
pp. E2636-E2645 ◽  
Author(s):  
Brandon J. DeKosky ◽  
Oana I. Lungu ◽  
Daechan Park ◽  
Erik L. Johnson ◽  
Wissam Charab ◽  
...  
Keyword(s):  
B Cells ◽  
Light Chain ◽  
Solvent Accessible Surface Area ◽  
Antibody Repertoire ◽  
Human Antibody ◽  
Variable Regions ◽  
Cell Immunity ◽  
Depth Analysis ◽  
Antibody Repertoires ◽  
Complementarity Determining Region

Elucidating how antigen exposure and selection shape the human antibody repertoire is fundamental to our understanding of B-cell immunity. We sequenced the paired heavy- and light-chain variable regions (VH and VL, respectively) from large populations of single B cells combined with computational modeling of antibody structures to evaluate sequence and structural features of human antibody repertoires at unprecedented depth. Analysis of a dataset comprising 55,000 antibody clusters from CD19+CD20+CD27− IgM-naive B cells, >120,000 antibody clusters from CD19+CD20+CD27+ antigen–experienced B cells, and >2,000 RosettaAntibody-predicted structural models across three healthy donors led to a number of key findings: (i) VH and VL gene sequences pair in a combinatorial fashion without detectable pairing restrictions at the population level; (ii) certain VH:VL gene pairs were significantly enriched or depleted in the antigen-experienced repertoire relative to the naive repertoire; (iii) antigen selection increased antibody paratope net charge and solvent-accessible surface area; and (iv) public heavy-chain third complementarity-determining region (CDR-H3) antibodies in the antigen-experienced repertoire showed signs of convergent paired light-chain genetic signatures, including shared light-chain third complementarity-determining region (CDR-L3) amino acid sequences and/or Vκ,λ–Jκ,λ genes. The data reported here address several longstanding questions regarding antibody repertoire selection and development and provide a benchmark for future repertoire-scale analyses of antibody responses to vaccination and disease.

scholarly journals Mouse Antibodies with Activity Against the SARS-CoV-2 D614G and B.1.351 Variants

2021 ◽  
Author(s):  
Larisa Troitskaya ◽  
Nelson Lap Shun Chan ◽  
Brendon Frank ◽  
Daniel Capon ◽  
Brian A. Zabel ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Severe Disease ◽  
Human Antibody ◽  
Human Antibodies ◽  
Rapid Spread ◽  
Antibody Repertoires ◽  
Murine Monoclonal Antibodies

With the rapid spread of SARS-CoV-2 variants, including those that are resistant to antibodies authorized for emergency use, it is apparent that new antibodies may be needed to effectively protect patients against more severe disease. Differences between the murine and human antibody repertoires may allow for the isolation of murine monoclonal antibodies that recognize a different or broader range of SARS-CoV-2 variants than the human antibodies that have been characterized so far. We describe mouse antibodies B13 and O24 that demonstrate neutralizing potency against SARS-CoV-2 Wuhan (D614G) and B.1.351 variants. Such murine antibodies may have advantages in protecting against severe symptoms when individuals are exposed to new SARS-CoV-2 variants.

scholarly journals A Putative Prophylactic Solution for COVID-19: Development of Novel Multiepitope Vaccine Candidate against SARS-COV-2 by Comprehensive Immunoinformatic and Molecular Modelling Approach

Biology ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 296
Author(s):  
Hafiz Muzzammel Rehman ◽  
Muhammad Usman Mirza ◽  
Mian Azhar Ahmad ◽  
Mahjabeen Saleem ◽  
Matheus Froeyen ◽  
...  
Keyword(s):  
Molecular Modelling ◽  
In Silico ◽  
Vaccine Development ◽  
Adaptive Immune Response ◽  
World Health ◽  
Vector System ◽  
T Cell Epitopes ◽  
Novel Coronavirus ◽  
Health Organization ◽  
Dynamics Simulations

The outbreak of 2019-novel coronavirus (SARS-CoV-2) that causes severe respiratory infection (COVID-19) has spread in China, and the World Health Organization has declared it a pandemic. However, no approved drug or vaccines are available, and treatment is mainly supportive and through a few repurposed drugs. The urgency of the situation requires the development of SARS-CoV-2-based vaccines. Immunoinformatic and molecular modelling are time-efficient methods that are generally used to accelerate the discovery and design of the candidate peptides for vaccine development. In recent years, the use of multiepitope vaccines has proved to be a promising immunization strategy against viruses and pathogens, thus inducing more comprehensive protective immunity. The current study demonstrated a comprehensive in silico strategy to design stable multiepitope vaccine construct (MVC) from B-cell and T-cell epitopes of essential SARS-CoV-2 proteins with the help of adjuvants and linkers. The integrated molecular dynamics simulations analysis revealed the stability of MVC and its interaction with human Toll-like receptors (TLRs), which trigger an innate and adaptive immune response. Later, the in silico cloning in a known pET28a vector system also estimated the possibility of MVC expression in Escherichia coli. Despite that this study lacks validation of this vaccine construct in terms of its efficacy, the current integrated strategy encompasses the initial multiple epitope vaccine design concepts. After validation, this MVC can be present as a better prophylactic solution against COVID-19.

Engineering therapeutic antibodies for patient safety: tackling the immunogenicity problem

2020 ◽  
Vol 33 ◽  
Author(s):  
Michael Ulitzka ◽  
Stefania Carrara ◽  
Julius Grzeschik ◽  
Henri Kornmann ◽  
Björn Hock ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Immune System ◽  
Immune Responses ◽  
Foreign Protein ◽  
Therapeutic Antibodies ◽  
T Cell Epitopes ◽  
Post Translational Modifications ◽  
Human Antibodies ◽  
Therapeutic Monoclonal Antibodies ◽  
In Silico Methods

Abstract Established monoclonal antibodies (mAbs) allow treatment of cancers, autoimmune diseases and other severe illnesses. Side effects either arise due to interaction with the target protein and its biology or result from of the patient’s immune system reacting to the foreign protein. This immunogenic reaction against therapeutic antibodies is dependent on various factors. The presence of non-human sequences can trigger immune responses as well as chemical and post-translational modifications of the antibody. However, even fully human antibodies can induce immune response through T cell epitopes or aggregates. In this review, we briefly describe, how therapeutic antibodies can interact with the patient’s immune system and summarize recent advancements in protein engineering and in silico methods to reduce immunogenicity of therapeutic monoclonal antibodies.

scholarly journals A Putative Prophylactic Solution for COVID-19: Development of Novel Multiepitope Vaccine Candidate against SARS‐COV‐2 by Comprehensive Immunoinformatic and Molecular Modelling Approach

2020 ◽  
Author(s):  
Hafiz Muzzammel Rehman ◽  
Muhammad Usman Mirza ◽  
Mahjabeen Saleem ◽  
Matheus Froeyen ◽  
Sarfraz Ahmad ◽  
...  
Keyword(s):  
Molecular Modelling ◽  
In Silico ◽  
Vaccine Development ◽  
Adaptive Immune Response ◽  
World Health ◽  
Vector System ◽  
T Cell Epitopes ◽  
Novel Coronavirus ◽  
Health Organization ◽  
Dynamics Simulations

The outbreak of 2019-novel coronavirus (SARS-CoV-2) that causes severe respiratory infection (COVID-19) has spread in China, and the world health organization declared it pandemic. However, no approved drug or vaccines are available, and treatment is mainly supportive and through a few repurposed drugs. In this urgency situation, development of SARS-CoV-2 based vaccines is immediately required. Immunoinformatic and molecular modelling are generally used time-efficient methods to accelerate the discovery and design of the candidate peptides for vaccine development. In recent years, the use of multiepitope vaccines is proved to be a promising immunization strategy against viruses and pathogens, which induce more comprehensive protective immunity. The current study demonstrated a comprehensive in-silico strategy to design stable multiepitope vaccine construct (MVC) from B-cell and T-cell epitopes of essential SARS-CoV-2 proteins with the help of adjuvants and linkers. The integrated molecular dynamics simulations analysis revealed the stability of MVC and its interaction with human Toll-like receptors (TLRs), which trigger an innate and adaptive immune response. Later, the in-silico cloning in a known pET28a vector system also estimated the possibility of MVC expression in E. Coli. Despite this study lacks validation of this vaccine construct in terms of its efficacy, the current integrated strategy encompasses the initial multiple epitope vaccine design concepts. After validation, this MVC can present to be a better prophylactic solution against COVID-19.

In silico approach for designing a novel recombinant fusion protein as a Candidate Vaccine against HPV

2020 ◽  
Vol 17 ◽  
Author(s):  
Mohsen Sisakht ◽  
Amir Mahmoodzadeh ◽  
Mohammadsaeid Zahedi ◽  
Davood Rostamzadeh ◽  
Amin Moradi Hasan-Abad ◽  
...  
Keyword(s):  
Immune Responses ◽  
Fusion Protein ◽  
In Silico ◽  
Precancerous Lesions ◽  
Candidate Vaccine ◽  
T Cell Epitopes ◽  
Binding Interaction ◽  
Hpv16 E6 ◽  
E7 Proteins

Background: Human papillomavirus (HPV) is the main biological agent causing sexually transmitted diseases (STDs), including precancerous lesions and several types of prevalent cancers. To date, numerous types of vaccines are designed to prevent high-risk HPV. However, their prophylactic effect is not the same and does not clear previous infections. Therefore, there is an urgent need for developing therapeutic vaccines that trigger cell-mediated immune responses for the treatment of HPV. The HPV16 E6 and E7 proteins are ideal targets for vaccine therapy against HPV. Fusion protein vaccines, which include both immunogenic interest protein and an adjuvant for augmenting the immunogenicity effects, are theoretically capable of guarantee the power of the immune system against HPV. Method: A vaccine construct, including HPV16 E6/E7 proteins along with a heat shock protein GP96 (E6/E7-NTGP96 construct), was designed using in silico methods. By the aid of the SWISS-MODEL server, the optimal 3D model of the designed vaccine was selected, followed by physicochemical and molecular parameters were performed using bioinformatics tools. Docking studies were done to evaluate the binding interaction of the vaccine. Allergenicity, immunogenicity, B, and T cell epitopes of the designed construct were predicted. Results: Immunological and structural computational results illustrated that our designed construct is potentially proper for stimulation of cellular and humoral immune responses against HPV. Conclusion: Computational studies showed that the E6/E7-NTGP96 construct is a promising candidate vaccine that needs further in vitro and in vivo evaluations.

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