Trends in therapeutic antibody affinity maturation: From in-vitro towards next-generation sequencing approaches

Tabasinezhad, Maryam; Talebkhan, Yeganeh; Wenzel, Wolfgang; Rahimi, Hamzeh; Omidinia, Eskandar; Mahboudi, Fereidoun

doi:10.1016/j.imlet.2019.06.009

Cited by 36 publications

(19 citation statements)

References 85 publications

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“…In the development of therapeutic proteins and antibodies, binding affinity is considerably one of the most crucial factors to achieve remarkable on-target activities in terms of high specific targeting and preferential localization in the diseased tissues (Thurber et al, 2008a(Thurber et al, , 2008bCarter, 2001). Thus, attempts have been made to improve the binding affinity for developing highly potent neutralizing antibodies through affinity maturation, although it is a time-consuming and laborious process (Tabasinezhad et al, 2019). However, there is still no clear criteria regarding the optimal affinity for the greatest in vivo efficacy, which increases iScience Article the dilemma of whether to proceed with affinity maturation.…”

Section: Discussionmentioning

confidence: 99%

“…Affinity maturation is an inevitable process for improving both the target specificities and therapeutic potencies of binding proteins during the lead optimization phase. Despite technical advances in molecular and computational biology, this process is still regarded as time-consuming and labor-intensive (Tabasinezhad et al, 2019). Moreover, given that a moderate binding affinity may result in the highest tumor penetration and accumulation rather than higher affinities, it can be expected that a study similar to a doseranging trial, exploring affinities, can be as effective as affinity maturation to improve therapeutic benefits.…”

Section: Discussionmentioning

confidence: 99%

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Dissecting the impact of target-binding kinetics of protein binders on tumor localization

et al. 2021

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Summary Systematic control of in vivo behavior of protein-based therapeutics is considered highly desirable for improving their clinical outcomes. Modulation of biochemical properties including molecular weight, surface charge, and binding affinity has thus been suggested to enhance their therapeutic effects. However, establishing a relationship between the binding affinity and tumor localization remains a debated issue. Here we investigate the influence of the binding affinity of proteins on tumor localization by using four repebodies having different affinities to EGFR. Biochemical analysis and molecular imaging provided direct evidence that optimal affinity with balanced target binding and dissociation can facilitate deep penetration and accumulation of protein binders in tumors by overcoming the binding-site-barrier effect. Our findings suggest that binding kinetics-based protein design can be implicated in the development of fine-tuned protein therapeutics for cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dissecting the impact of target-binding kinetics of protein binders on tumor localization

et al. 2021

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“…During clonal selection in the germinal center, only B-cells with the highest affinity can expand and produce vast amounts of antibodies 24. Advances in in vitro affinity maturation enabled researchers to develop antibodies with even higher affinities to their targets making these antibodies desirable in many fields of research 25. Furthermore, as mAbs are mainly produced in mice, these antibodies elicit an immune response resulting in the production of human-anti-mouse-antibodies (HAMAs) which interfere with the treatment 26.…”

Section: Molecular Imaging Componentsmentioning

confidence: 99%

Monoclonal antibody-based molecular imaging strategies and theranostic opportunities

Dammes

Peer

2020

Theranostics

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Molecular imaging modalities hold great potential as less invasive techniques for diagnosis and management of various diseases. Molecular imaging combines imaging agents with targeting moieties to specifically image diseased sites in the body. Monoclonal antibodies (mAbs) have become increasingly popular as novel therapeutics against a variety of diseases due to their specificity, affinity and serum stability. Because of the same properties, mAbs are also exploited in molecular imaging to target imaging agents such as radionuclides to the cell of interest in vivo. Many studies investigated the use of mAb-targeted imaging for a variety of purposes, for instance to monitor disease progression and to predict response to a specific therapeutic agent. Herein, we highlighted the application of mAb-targeted imaging in three different types of pathologies: autoimmune diseases, oncology and cardiovascular diseases. We also described the potential of molecular imaging strategies in theranostics and precision medicine. Due to the nearly infinite repertoire of mAbs, molecular imaging can change the future of modern medicine by revolutionizing diagnostics and response prediction in practically any disease.

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“…phage, yeast, ribosome, etc.). More recent review of such experimental methodologies has been discussed by Tabasinezhad et al 62 and Lim et al 63 Furthermore, to complement experimental techniques, structural and computational techniques continue to emerge and evolve to aid in the affinity maturation process.…”

Section: Engineering a New Generation Of Vhh Domains Vhh Domain Developmentmentioning

confidence: 99%

Structure and development of single domain antibodies as modules for therapeutics and diagnostics

Hoey

Eom

Horn

2019

Exp Biol Med (Maywood)

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Since their discovery just over 25 years ago, the single variable domain from heavy-chain-only antibodies plays a role in an increasing number of antibody-based applications. Structural and biophysical studies have revealed that the small, ∼15 kDa, single variable domain found in camelids displays versatility in target recognition. Such insight has served as the foundation to develop and engineer VHH domains with enhanced properties capable of targeting a range of therapeutically relevant protein antigens or low-molecular weight haptens. Furthermore, the modular nature of VHH domains allows them to be introduced into constructs that are simply not possible with conventional antibodies. Here, we review the structural and biophysical properties of VHH domains, highlight recent VHH-based therapeutics and diagnostics, and provide insight into VHH engineering that may pave the way to next-generation single domain antibody applications. Impact statement The development of novel antibody formats, beyond conventional antibodies, opens new possibilities in medical therapies, diagnostics, and general life science applications requiring affinity reagents. The camelid VHH domain, from heavy-chain-only antibodies, has emerged as a jack-of-all-trades module for novel affinity reagents. Applications include targeted cancer therapies, novel antimicrobial agents, conformation specific reagents, and tailor-made molecular switch entities. The breadth of unique uses for the VHH will continue to grow, opening new opportunities to treat and understand disease.

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Trends in therapeutic antibody affinity maturation: From in-vitro towards next-generation sequencing approaches

Cited by 36 publications

References 85 publications

Dissecting the impact of target-binding kinetics of protein binders on tumor localization

Dissecting the impact of target-binding kinetics of protein binders on tumor localization

Monoclonal antibody-based molecular imaging strategies and theranostic opportunities

Structure and development of single domain antibodies as modules for therapeutics and diagnostics

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