Prospects of PASylation® for the design of protein and peptide therapeutics with extended half-life and enhanced action

Gebauer, Michaela; Skerra, Arne

doi:10.1016/j.bmc.2017.09.016

Cited by 53 publications

(34 citation statements)

References 80 publications

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“…Although binding of Coversin to C5 and to LTB 4 is functionally independent (15,16), binding of C5 to Coversin indirectly affects its ability to sequester LTB 4 over long periods because binding to C5 prolongs the half-life of Coversin in the murine circulation from less than 20 minutes to approximately 10 hours (13). The half-life of Coversin in the circulation of mice when not bound to C5 can be extended to 10.2 hours by PASylation, which is the in-frame N-terminal fusion of a 600-amino acid tail composed of repetitions of the tripeptide sequence Pro Ala Ser to Coversin, thus, yielding PAS-Coversin (17,18). The extension of the half-life by PASylation is important for the clinical development of L-Coversin, a bioengineered variant of Coversin mutated at 7 amino acids to ablate binding to C5, which therefore .…”

Section: To Omci Have Nomentioning

confidence: 99%

Dual inhibition of complement factor 5 and leukotriene B4 synergistically suppresses murine pemphigoid disease

et al. 2019

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Section: To Omci Have Nomentioning

confidence: 99%

Dual inhibition of complement factor 5 and leukotriene B4 synergistically suppresses murine pemphigoid disease

et al. 2019

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“…In a preclinical study, we systematically examined the impact of plasma half-life of modified Fab fragments in a HER2-positive breast cancer model [12]. Tailoring of plasma half-life was conveniently achieved using the PASylation technology [12][13][14]. To this end, conformationally disordered 100-600 residue chains consisting of Pro, Ala, and Ser (PAS 100-600 ) were genetically fused to the C-terminus of the light chain of the trastuzumab Fab ( Fig.…”

Section: Introductionmentioning

confidence: 99%

First In-Human Medical Imaging with a PASylated 89Zr-Labeled Anti-HER2 Fab-Fragment in a Patient with Metastatic Breast Cancer

Richter

Knorr

Schlapschy

et al. 2020

Nucl Med Mol Imaging

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Purpose PASylation® offers the ability to systematically tune and optimize the pharmacokinetics of protein tracers for molecular imaging. Here we report the first clinical translation of a PASylated Fab fragment (89 Zr•Df-HER2-Fab-PAS 200) for the molecular imaging of tumor-related HER2 expression. Methods A patient with HER2-positive metastatic breast cancer received 37 MBq of 89 Zr•Df-HER2-Fab-PAS 200 at a total mass dose of 70 μg. PET/CT was carried out 6, 24, and 45 h after injection, followed by image analysis of biodistribution, normal organ uptake, and lesion targeting. Results Images show a biodistribution typical for protein tracers, characterized by a prominent blood pool 6 h p.i., which decreased over time. Lesions were detectable as early as 24 h p.i. 89 Zr•Df-HER2-Fab-PAS 200 was tolerated well. Conclusion This study demonstrates that a PASylated Fab tracer shows appropriate blood clearance to allow sensitive visualization of small tumor lesions in a clinical setting.

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“…However, the use of structurally disordered polypeptides as precipitants has not been reported to date. Proline/alaninerich sequences (PAS) represent a novel class of biodegradable biopolymers that are currently under development as a biological alternative to PEG for extension of the plasma half-life of therapeutic proteins (Gebauer & Skerra, 2018;Schlapschy et al, 2013). PAS polymers, which consist of the small uncharged proteinogenic l-amino acids proline, alanine and/or serine ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Proline/alanine-rich sequence (PAS) polypeptides as an alternative to PEG precipitants for protein crystallization

Schiefner¹,

Walser²,

Gebauer³

et al. 2020

Acta Crystallogr F Struct Biol Commun

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Proline/alanine-rich sequence (PAS) polypeptides represent a novel class of biosynthetic polymers comprising repetitive sequences of the small proteinogenic amino acids L-proline, L-alanine and/or L-serine. PAS polymers are strongly hydrophilic and highly soluble in water, where they exhibit a natively disordered conformation without any detectable secondary or tertiary structure, similar to polyethylene glycol (PEG), which constitutes the most widely applied precipitant for protein crystallization to date. To investigate the potential of PAS polymers for structural studies by X-ray crystallography, two proteins that were successfully crystallized using PEG in the past, hen egg-white lysozyme and the Fragaria × ananassa O-methyltransferase, were subjected to crystallization screens with a 200-residue PAS polypeptide. The PAS polymer was applied as a precipitant using a vapor-diffusion setup that allowed individual optimization of the precipitant concentration in the droplet in the reservoir. As a result, crystals of both proteins showing high diffraction quality were obtained using the PAS precipitant. The genetic definition and precise macromolecular composition of PAS polymers, both in sequence and in length, distinguish them from all natural and synthetic polymers that have been utilized for protein crystallization so far, including PEG, and facilitate their adaptation for future applications. Thus, PAS polymers offer potential as novel precipitants for biomolecular crystallography.

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Prospects of PASylation® for the design of protein and peptide therapeutics with extended half-life and enhanced action

Cited by 53 publications

References 80 publications

Dual inhibition of complement factor 5 and leukotriene B4 synergistically suppresses murine pemphigoid disease

Dual inhibition of complement factor 5 and leukotriene B4 synergistically suppresses murine pemphigoid disease

First In-Human Medical Imaging with a PASylated 89Zr-Labeled Anti-HER2 Fab-Fragment in a Patient with Metastatic Breast Cancer

Proline/alanine-rich sequence (PAS) polypeptides as an alternative to PEG precipitants for protein crystallization

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