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 Immunogenicity of Innovative and Biosimilar Monoclonal Antibodies

Antibodies ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 21 ◽  
Author(s):  
Erik Doevendans ◽  
Huub Schellekens
Keyword(s):  
Monoclonal Antibodies ◽  
Immune System ◽  
First Generation ◽  
Chimeric Antibodies ◽  
Human Antibodies ◽  
Limited Efficacy ◽  
Hybridoma Technology ◽  
Infusion Reactions ◽  
Opening Up ◽  
High Immunogenicity

The development of hybridoma technology for producing monoclonal antibodies (mAbs) by Kohler and Milstein (1975) counts as one of the major medical breakthroughs, opening up endless possibilities for research, diagnosis and for treatment of a whole variety of diseases. Therapeutic mAbs were introduced three decades ago. The first generation of therapeutic mAbs of murine origin showed high immunogenicity, which limited efficacy and was associated with severe infusion reactions. Subsequently chimeric, humanized, and fully human antibodies were introduced as therapeutics, these mAbs were considerably less immunogenic. Unexpectedly humanized mAbs generally show similar immunogenicity as chimeric antibodies; based on sequence homology chimeric mAbs are sometimes more “human” than humanized mAbs. With the introduction of the regulatory concept of similar biological medicines (biosimilars) a key concern is the similarity in terms of immunogenicity of these biosimilars with their originators. This review focuses briefly on the mechanisms of induction of immunogenicity by biopharmaceuticals, mAbs in particular, in relation to the target of the immune system.

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 Exploring antibody repurposing for COVID-19: beyond presumed roles of therapeutic antibodies

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Puneet Rawat ◽  
Divya Sharma ◽  
Ambuj Srivastava ◽  
Vani Janakiraman ◽  
M. Michael Gromiha
Keyword(s):  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Neutralizing Antibodies ◽  
Effective Vaccine ◽  
Therapeutic Antibodies ◽  
Viral Neutralization ◽  
Investigational Drugs ◽  
Therapeutic Monoclonal Antibodies ◽  
Interaction Surface ◽  
Limited Choice

AbstractThe urgent need for a treatment of COVID-19 has left researchers with limited choice of either developing an effective vaccine or identifying approved/investigational drugs developed for other medical conditions for potential repurposing, thus bypassing long clinical trials. In this work, we compared the sequences of experimentally verified SARS-CoV-2 neutralizing antibodies and sequentially/structurally similar commercialized therapeutic monoclonal antibodies. We have identified three therapeutic antibodies, Tremelimumab, Ipilimumab and Afasevikumab. Interestingly, these antibodies target CTLA4 and IL17A, levels of which have been shown to be elevated during severe SARS-CoV-2 infection. The candidate antibodies were evaluated further for epitope restriction, interaction energy and interaction surface to gauge their repurposability to tackle SARS-CoV-2 infection. Our work provides candidate antibody scaffolds with dual activities of plausible viral neutralization and immunosuppression. Further, these candidate antibodies can also be explored in diagnostic test kits for SARS-CoV-2 infection. We opine that this in silico workflow to screen and analyze antibodies for repurposing would have widespread applications.

Therapeutic potential of immunostimulatory monoclonal antibodies

2006 ◽  
Vol 111 (2) ◽  
pp. 93-106 ◽  
Author(s):  
Juliet C. Gray ◽  
Peter W. M. Johnson ◽  
Martin J. Glennie
Keyword(s):  
Monoclonal Antibodies ◽  
Immune System ◽  
Immune Responses ◽  
Therapeutic Potential ◽  
Therapeutic Agents ◽  
New Approach ◽  
Advantages And Disadvantages ◽  
Cell Responses ◽  
Enhance Antigen Presentation

The aim of cancer immunotherapy is to employ the specificity of the immune system to provide a more effective, less toxic, treatment compared with conventional therapies. Although many strategies have been used to try to generate effective anticancer immune responses, very few have reached mainstream clinical use. A new approach introduced over the last few years is to use immunostimulatory mAbs (monoclonal antibodies) to boost weak endogenous antitumour immune responses to levels which are therapeutic. Such agonistic or antagonistic mAbs bind to key receptors in the immune system acting to enhance antigen presentation, provide co-stimulation or to counteract immunoregulation. In animal models, this approach has been shown to promote powerful tumour-specific T-cell responses capable of clearing established tumour and leaving the animal with long-term immunity. In addition to this impressive therapy seen in tumour models, these same mAbs also have the potential to be therapeutically useful in autoimmune and infectious diseases. This review discusses the use of these mAbs as therapeutic agents, their advantages and disadvantages and the challenges that need to be overcome to use them clinically.

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 Unswitched immunoglobulin M response prolongs mouse survival in prion disease

2009 ◽  
Vol 90 (3) ◽  
pp. 777-782 ◽  
Author(s):  
Mourad Tayebi ◽  
John Collinge ◽  
Simon Hawke
Keyword(s):  
Monoclonal Antibodies ◽  
Immune System ◽  
Immune Responses ◽  
Prion Disease ◽  
Immunoglobulin M ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
Prolonged Incubation ◽  
Resistant Form ◽  
Antigen Presenting

Several studies have failed to demonstrate the presence of immune responses to infectious prions during the course of prion disease, reflecting the identical primary structure of normal and disease-associated isoforms and the widespread expression of the normal cellular form of prion protein, PrPC, leading to B- and/or T-cell tolerance of disease-associated isoforms and also possibly because antigen-presenting cells are unable to process the highly aggregated, detergent-insoluble, protease-resistant form, PrPSc. Under certain circumstances, PrPSc can be revealed to the immune system in immunogenic form, and it has been shown previously that anti-PrP antibodies can be induced to prions immunoadsorbed to Dynabeads using specific anti-PrP monoclonal antibodies, even in PrP-sufficient mice. This study demonstrated in a murine scrapie model that PrP–Dynabeads effectively stimulated the immune system to produce anti-PrP IgM antibodies over prolonged periods after repeated immunization. It was also shown that these immune responses prolonged incubation times in murine scrapie.

scholarly journals The Relevance of Monoclonal Antibodies in the Treatment of COVID-19

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 557
Author(s):  
Anabel Torrente-López ◽  
Jesús Hermosilla ◽  
Natalia Navas ◽  
Luis Cuadros-Rodríguez ◽  
José Cabeza ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Immune System ◽  
State Of The Art ◽  
Virus Protein ◽  
Immune Disorders ◽  
The Subject ◽  
New Treatments ◽  
Therapeutic Monoclonal Antibodies ◽  
Made In

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.

A cell-based FcRn-dependent recycling assay for predictive pharmacokinetic assessment of therapeutic antibodies

Bioanalysis ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 1135-1144
Author(s):  
Chang Liu ◽  
Yeon Su Kim ◽  
John Hok-Nin Lowe ◽  
Shan Chung
Keyword(s):  
Monoclonal Antibodies ◽  
Fc Receptor ◽  
Strongly Correlated ◽  
Therapeutic Antibodies ◽  
Neonatal Fc Receptor ◽  
Pharmacokinetic Assessment ◽  
Pharmacokinetic Properties ◽  
A Cell ◽  
Therapeutic Monoclonal Antibodies ◽  
Selection Of

Aim: Evaluation of suitable pharmacokinetic properties is critical for successful development of IgG-based biotherapeutics. The prolonged half-lives of IgGs depend on the intracellular trafficking function of neonatal Fc receptor, which rescues internalized IgGs from lysosomal degradation and recycles them back to circulation. Results: Here, we developed a novel cell-based assay to quantify recycling of monoclonal antibodies in a transwell culture system that uses a cell line that stably expresses human neonatal Fc receptor. We tested seven therapeutic antibodies and showed that the recycling output of the assay strongly correlated with the clearance in humans. Conclusion: This recycling assay has potential application as a pharmacokinetic prescreening tool to facilitate development and selection of IgG-based candidate therapeutic monoclonal antibodies.

scholarly journals Broadly-Neutralizing Antibodies Against Emerging SARS-CoV-2 Variants

2021 ◽  
Vol 12 ◽  
Author(s):  
Lok Bahadur Shrestha ◽  
Nicodemus Tedla ◽  
Rowena A. Bull
Keyword(s):  
Monoclonal Antibodies ◽  
Severe Acute Respiratory Syndrome ◽  
Neutralizing Antibodies ◽  
Second Generation ◽  
Therapeutic Antibodies ◽  
Broadly Neutralizing Antibodies ◽  
Escape Mutants ◽  
Cross Neutralization ◽  
A Priority ◽  
Therapeutic Monoclonal Antibodies

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have become a major concern in the containment of current pandemic. The variants, including B.1.1.7 (Alpha), B.1.351 (Beta), P1 (Gamma) and B.1.617.2 (Delta) have shown reduced sensitivity to monoclonal antibodies, plasma and/or sera obtained from convalescent patients and vaccinated individuals. Development of potent therapeutic monoclonal antibodies (mAbs) with broad neutralizing breadth have become a priority for alleviating the devastating effects of this pandemic. Here, we review some of the most promising broadly neutralizing antibodies obtained from plasma of patients that recovered from early variants of SARS-CoV-2 that may be effective against emerging new variants of the virus. This review summarizes several mAbs, that have been discovered to cross-neutralize across Sarbecoviruses and SARS-CoV-2 escape mutants. Understanding the characteristics that confer this broad and cross-neutralization functions of these mAbs would inform on the development of therapeutic antibodies and guide the discovery of second-generation vaccines.

Sign in / Sign up

Export Citation Format

Share Document