Understanding and overcoming trade-offs between antibody affinity, specificity, stability and solubility

Rabia, Lilia A.; Desai, Alec A.; Jhajj, Harkamal S.; Tessier, Peter M.

doi:10.1016/j.bej.2018.06.003

Cited by 106 publications

(84 citation statements)

References 82 publications

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“…There is a complex interplay between properties such as affinity, specificity, and stability that must be cooptimized to generate molecules with the desired characteristics. 311 In contrast to rational mutagenesis, evolutionary approaches generate libraries of variants and isolate those with enhanced biophysical properties by screening under destabilizing conditions. 300 Several methods exist for assessing the conformational stability and aggregation propensity of drug candidates, as well as related properties such as colloidal stability and self-association.…”

Section: Stability and Aggregationmentioning

confidence: 99%

Considerations for the Design of Antibody-Based Therapeutics

Goulet

Atkins

2020

Journal of Pharmaceutical Sciences

161

154

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Keywords: antibody(s) antibody drug(s) antibody drug conjugate(s) (ADC) physicochemical properties pharmacokinetics monoclonal antibody(s) immunotherapy IgG antibody(s) drug design developability a b s t r a c t Antibody-based proteins have become an important class of biologic therapeutics, due in large part to the stability, specificity, and adaptability of the antibody framework. Indeed, antibodies not only have the inherent ability to bind both antigens and endogenous immune receptors but also have proven extremely amenable to protein engineering. Thus, several derivatives of the monoclonal antibody format, including bispecific antibodies, antibody-drug conjugates, and antibody fragments, have demonstrated efficacy for treating human disease, particularly in the fields of immunology and oncology. Reviewed here are considerations for the design of antibody-based therapeutics, including immunological context, therapeutic mechanisms, and engineering strategies. First, characteristics of antibodies are introduced, with emphasis on structural domains, functionally important receptors, isotypic and allotypic differences, and modifications such as glycosylation. Then, aspects of therapeutic antibody design are discussed, including identification of antigen-specific variable regions, choice of expression system, use of multispecific formats, and design of antibody derivatives based on fragmentation, oligomerization, or conjugation to other functional moieties. Finally, strategies to enhance antibody function through protein engineering are reviewed while highlighting the impact of fundamental biophysical properties on protein developability.

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Section: Stability and Aggregationmentioning

confidence: 99%

Considerations for the Design of Antibody-Based Therapeutics

Goulet

Atkins

2020

Journal of Pharmaceutical Sciences

161

154

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“…However, in real-world applications, not only conformational stability, but also other properties, such as colloidal stability, have to be considered, and trade-offs between properties have been reported. 12 In one such example, Broom et al 142 built a meta-predictor that combined 11 freely available DDG prediction tools. They showed that the accuracy of the predictions was better than that of individual tools against 605 experimentally verified mutations.…”

Section: Predicted Ddg As a Selection Criterionmentioning

confidence: 99%

“…11 The trade-off between binding affinity and other properties is known to be an issue of antibody engineering. 12 Improving other properties such as stability, viscosity, and immunogenicity can therefore be realized by changing the amino acids of the non-CDR parts of antibodies. Careful inspection of mutational sites is often necessary to generate better antibodies.…”

Section: Introductionmentioning

confidence: 99%

Engineering Stability, Viscosity, and Immunogenicity of Antibodies by Computational Design

Kuroda

Tsumoto

2020

Journal of Pharmaceutical Sciences

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In recent years, computational methods have garnered much attention in protein engineering. A large number of computational methods have been developed to analyze the sequences and structures of proteins and have been used to predict the various properties. Antibodies are one of the emergent protein therapeutics, and thus, methods to control their physicochemical properties are highly desirable. However, despite the tremendous efforts of past decades, computational methods to predict the physicochemical properties of antibodies are still in their infancy. Experimental validations are certainly required for real-world applications, and the results should be interpreted with caution. Among the various properties of antibodies, we focus in this review on stability, viscosity, and immunogenicity, and we present the current status of computational methods to engineer such properties.

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“…The active sites of antibodies, like enzymes, are commonly engineered to increase their function, and trade‐offs between activity and stability are also commonplace for antibodies . In some ways, directed evolution of antibodies is simpler than for enzymes because it is easier to screen for antibody function (binding to target antigens) than it is to screen for enzyme activity.…”

Section: Directed Evolution Methods For Selecting Proteins With High mentioning

confidence: 99%

Directed evolution methods for overcoming trade‐offs between protein activity and stability

2019

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Engineered proteins are being widely developed and employed in applications ranging from enzyme catalysts to therapeutic antibodies. Directed evolution, an iterative experimental process composed of mutagenesis and library screening, is a powerful technique for enhancing existing protein activities and generating entirely new ones not observed in nature. However, the process of accumulating mutations for enhanced protein activity requires chemical and structural changes that are often destabilizing, and low protein stability is a significant barrier to achieving large enhancements in activity during multiple rounds of directed evolution. Here we highlight advances in understanding the origins of protein activity/stability trade-offs for two important classes of proteins (enzymes and antibodies) as well as innovative experimental and computational methods for overcoming such trade-offs. These advances hold great potential for improving the generation of highly active and stable proteins that are needed to address key challenges related to human health, energy and the environment. K E Y W O R D Saffinity, antibody, catalysis, enzyme, protein design, protein engineering

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Understanding and overcoming trade-offs between antibody affinity, specificity, stability and solubility

Cited by 106 publications

References 82 publications

Considerations for the Design of Antibody-Based Therapeutics

Considerations for the Design of Antibody-Based Therapeutics

Engineering Stability, Viscosity, and Immunogenicity of Antibodies by Computational Design

Directed evolution methods for overcoming trade‐offs between protein activity and stability

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