Affibody Molecules in Biotechnological and Medical Applications

Ståhl, Stefan; Gräslund, Torbjörn; Karlström, Amelie Eriksson; Frejd, Fredrik Y.; Nygren, Per‐Åke; Löfblom, John

doi:10.1016/j.tibtech.2017.04.007

Cited by 282 publications

(250 citation statements)

References 143 publications

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“…Affibody molecules are currently evaluated as targeting moieties for radionuclide molecular imaging (Ståhl et al 2017). Affibody molecules (6–7 kDa) are robust three-helical proteins developed using the scaffold of the 58-amino acid-long Z domain of staphylococcal protein A. Affibody molecules are highly soluble and can refold with high fidelity after thermal or chemical denaturation (Arora et al 2004), which permits the use of harsh labeling condition and expands the number of applicable labeling methods.…”

Section: Introductionmentioning

confidence: 99%

“…Their small size makes it possible to obtain higher-contrast images in comparison to bulky monoclonal antibodies (150-kDa). Combination of small size, high affinity and specificity makes affibody molecules suitable ligands for both molecular imaging and therapeutic applications (Lofblom et al 2010; Tolmachev et al 2007; Ståhl et al 2017). Clinical and preclinical studies have indicated that affibody molecules can provide high sensitivity and specificity for visualizing several targets in cancer xenografts, e.g.…”

Section: Introductionmentioning

confidence: 99%

“…Clinical and preclinical studies have indicated that affibody molecules can provide high sensitivity and specificity for visualizing several targets in cancer xenografts, e.g. human epidermal growth factor 2 (HER2), human epidermal growth factor receptor type 3 (HER3), insulin-like growth factor 1 receptor (IGF-1R), platelet-derived growth factor receptor β (PDGFRβ) and carbonic anhydrase IX (CAIX) using single photon emission computed tomography (SPECT) and positron emission tomography (PET) techniques (Ståhl et al 2017). …”

Section: Introductionmentioning

confidence: 99%

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Influence of composition of cysteine-containing peptide-based chelators on biodistribution of 99mTc-labeled anti-EGFR affibody molecules

et al. 2018

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Epidermal growth factor receptor (EGFR) is overexpressed in a number of cancers and is the molecular target for several anti-cancer therapeutics. Radionuclide molecular imaging of EGFR expression should enable personalization of anti-cancer treatment. Affibody molecule is a promising type of high-affinity imaging probes based on a non-immunoglobulin scaffold. A series of derivatives of the anti-EGFR affibody molecule ZEGFR:2377, having peptide-based cysteine-containing chelators for conjugation of 99mTc, was designed and evaluated. It was found that glutamate-containing chelators Gly-Gly-Glu-Cys (GGEC), Gly-Glu-Glu-Cys (GEEC) and Glu-Glu-Glu-Cys (EEEC) provide the best labeling stability. The glutamate containing conjugates bound to EGFR-expressing cells specifically and with high affinity. Specific targeting of EGFR-expressing xenografts in mice was demonstrated. The number of glutamate residues in the chelator had strong influence on biodistribution of radiolabeled affibody molecules. Increase of glutamate content was associated with lower uptake in normal tissues. The 99mTc-labeled variant containing the EEEC chelator provided the highest tumor-to-organ ratios. In conclusion, optimizing the composition of peptide-based chelators enhances contrast of imaging of EGFR-expression using affibody molecules.Electronic supplementary materialThe online version of this article (10.1007/s00726-018-2571-1) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Influence of composition of cysteine-containing peptide-based chelators on biodistribution of 99mTc-labeled anti-EGFR affibody molecules

et al. 2018

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“…The same principles can hypothetically be applied to improve the bioavailability of small proteins with therapeutic potential. Affibody molecules are a class of small (58 aa) proteins with great potential as alternatives to monoclonal antibodies as therapeutic targeting proteins . Affibody molecules are so‐called engineered scaffold proteins (ESPs), which typically are selected from combinatorial libraries based on a protein scaffold.…”

Section: Introductionmentioning

confidence: 99%

“…In this study, we have explored stabilization towards intestinal proteases through the introduction of intramolecular thioether bridges into an affibody molecule that binds the epidermal growth factor receptor (EGFR), which is known to be overexpressed in a number of different cancers . This affibody was chosen for study because it binds a molecular target that is of therapeutic relevance for treatment of, for example, lung cancer, but it also serves as a prototype for the panel of available affibody molecules, binding targets such as human epidermal growth factor receptor 3 (HER3), insulin‐like growth factor 1 receptor (IGF‐1R), and interleukin‐6 (IL‐6) . The incorporation of thioether bridges instead of disulfide bridges, which are more commonly used in protein engineering, was motivated by their superior stability to reducing environments and by the reduced risk of thiol–disulfide exchange with endogenous proteins .…”

Section: Introductionmentioning

confidence: 99%

Intramolecular Thioether Crosslinking to Increase the Proteolytic Stability of Affibody Molecules

2017

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Protein therapeutics suffer from low oral bioavailability, mainly due to poor membrane permeability and digestion by gastrointestinal proteases. To improve proteolytic stability, intramolecular thioether crosslinks were introduced into a three-helix affibody molecule binding the human epidermal growth factor receptor (EGFR). Solid-phase peptide synthesis was used to produce an unmodified control protein domain and three different crosslinked protein domain variants: one with a thioether crosslink between the N-terminal lysine residue and a cysteine residue in the second loop region (denoted K4), a second with a crosslink between the C-terminal lysine residue and a cysteine residue in the first loop region (denoted K58), and a third with crosslinks in both positions (denoted K4K58). Circular dichroism (CD) and surface-plasmon-resonance-based (SPR-based) biosensor studies of the protein domains showed that the three-helix structure and high-affinity binding to EGFR were preserved in the crosslinked protein domains. In vitro digestion by gastrointestinal proteases demonstrated that the crosslinked protein domains showed increased stability towards pepsin and towards a combination of trypsin and chymotrypsin.

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Genetically Engineered Cellular Membrane Vesicles as Tailorable Shells for Therapeutics

Ren

Liu

et al. 2021

Advanced Science

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Benefiting from the blooming interaction of nanotechnology and biotechnology, biosynthetic cellular membrane vesicles (Bio-MVs) have shown superior characteristics for therapeutic transportation because of their hydrophilic cavity and hydrophobic bilayer structure, as well as their inherent biocompatibility and negligible immunogenicity. These excellent cell-like features with specific functional protein expression on the surface can invoke their remarkable ability for Bio-MVs based recombinant protein therapy to facilitate the advanced synergy in poly-therapy. To date, various tactics have been developed for Bio-MVs surface modification with functional proteins through hydrophobic insertion or multivalent electrostatic interactions. While the Bio-MVs grow through genetically engineering strategies can maintain binding specificity, sort orders, and lead to strict information about artificial proteins in a facile and sustainable way. In this progress report, the most current technology of Bio-MVs is discussed, with an emphasis on their multi-functionalities as "tailorable shells" for delivering bio-functional moieties and therapeutic entities. The most notable success and challenges via genetically engineered tactics to achieve the new generation of Bio-MVs are highlighted. Besides, future perspectives of Bio-MVs in novel bio-nanotherapy are provided.

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Affibody Molecules in Biotechnological and Medical Applications

Cited by 282 publications

References 143 publications

Influence of composition of cysteine-containing peptide-based chelators on biodistribution of 99mTc-labeled anti-EGFR affibody molecules

Influence of composition of cysteine-containing peptide-based chelators on biodistribution of 99mTc-labeled anti-EGFR affibody molecules

Intramolecular Thioether Crosslinking to Increase the Proteolytic Stability of Affibody Molecules

Genetically Engineered Cellular Membrane Vesicles as Tailorable Shells for Therapeutics

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