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 Immunotoxin Screening System: A Rapid and Direct Approach to Obtain Functional Antibodies with Internalization Capacities

Toxins ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 658
Author(s):  
Shusei Hamamichi ◽  
Takeshi Fukuhara ◽  
Nobutaka Hattori
Keyword(s):  
Monoclonal Antibodies ◽  
Screening Strategy ◽  
Screening System ◽  
Experimental Conditions ◽  
Drug Conjugates ◽  
System A ◽  
A Cell ◽  
Functional Antibodies ◽  
Therapeutic Monoclonal Antibodies ◽  
Selection Of

Toxins, while harmful and potentially lethal, have been engineered to develop potent therapeutics including cytotoxins and immunotoxins (ITs), which are modalities with highly selective targeting capabilities. Currently, three cytotoxins and IT are FDA-approved for treatment of multiple forms of hematological cancer, and additional ITs are tested in the clinical trials or at the preclinical level. For next generation of ITs, as well as antibody-mediated drug delivery systems, specific targeting by monoclonal antibodies is critical to enhance efficacies and reduce side effects, and this methodological field remains open to discover potent therapeutic monoclonal antibodies. Here, we describe our application of engineered toxin termed a cell-based IT screening system. This unique screening strategy offers the following advantages: (1) identification of monoclonal antibodies that recognize cell-surface molecules, (2) selection of the antibodies that are internalized into the cells, (3) selection of the antibodies that induce cytotoxicity since they are linked with toxins, and (4) determination of state-specific activities of the antibodies by differential screening under multiple experimental conditions. Since the functional monoclonal antibodies with internalization capacities have been identified successfully, we have pursued their subsequent modifications beyond antibody drug conjugates, resulting in development of immunoliposomes. Collectively, this screening system by using engineered toxin is a versatile platform, which enables straight-forward and rapid selection for discovery of novel functional antibodies.

Neonatal Fc receptor (FcRn): a novel target for therapeutic antibodies and antibody engineering

2014 ◽  
Vol 22 (4) ◽  
pp. 269-278 ◽  
Author(s):  
Yuan Wang ◽  
Zehua Tian ◽  
Diraviyam Thirumalai ◽  
Xiaoying Zhang
Keyword(s):  
Fc Receptor ◽  
Antibody Engineering ◽  
Therapeutic Antibodies ◽  
Neonatal Fc Receptor ◽  
Novel Target

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.

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 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.

scholarly journals Efflux of monoclonal antibodies from rat brain by neonatal Fc receptor, FcRn

2013 ◽  
Vol 1534 ◽  
pp. 13-21 ◽  
Author(s):  
Philip R. Cooper ◽  
Gary J. Ciambrone ◽  
Connie M. Kliwinski ◽  
Eva Maze ◽  
Lowell Johnson ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Rat Brain ◽  
Fc Receptor ◽  
Neonatal Fc Receptor
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