Challenges and advancements in the pharmacokinetic enhancement of therapeutic proteins

Khodabakhsh, Farnaz; Salimian, Morteza; Hedayati, Maryam; Cohan, Reza Ahangari; Norouzian, Dariush

doi:10.1080/10826068.2020.1839907

Cited by 19 publications

(6 citation statements)

References 76 publications

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“…While bivalency (F(ab) 2 or Minibodies) can lead to an avidity effect, differences in the macromolecular size considerably influence the glomerular filtration rate and, thus, influence the half-life in circulation. Of note, in all these formats, the absence of the immunoglobulin Fc region, which effects endosomal recycling, leads to much faster elimination from plasma compared with intact MAbs . However, for radioligands intended for diagnostic imaging, a shorter plasma half-life in combination with short-lived radioisotopes has proven advantageous in clinical practice as it allows tracer administration and imaging of the patient on the same day .…”

Section: Introductionmentioning

confidence: 99%

“…Of note, in all these formats, the absence of the immunoglobulin Fc region, which effects endosomal recycling, leads to much faster elimination from plasma compared with intact MAbs. 18 However, for radioligands intended for diagnostic imaging, a shorter plasma half-life in combination with short-lived radioisotopes has proven advantageous in clinical practice as it allows tracer administration and imaging of the patient on the same day. 19 Nevertheless, we were previously able to demonstrate that moderate extension of the plasma half-life for small antibody fragments using PASylation technology 20 leads to enhanced tumor contrast, most likely due to longer contact time of the PET radioligand with the malignant tissue, which favors accumulation.…”

Section: ■ Introductionmentioning

confidence: 99%

“…21 (iii) The availability of β + -emitting radioisotopes suitable for protein labeling is limited. Currently, 18 F, 68 Ga, 64 Cu, 89 Zr, and 124 I are predominantly used. 19,22−24 68 Ga is often utilized for diagnostic purposes due to its short half-life of 68 min and the facile supply using 68 Ge/ 68 Ga generators, independent of onsite cyclotrons.…”

Section: ■ Introductionmentioning

confidence: 99%

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Molecular Design of ⁶⁸Ga- and ⁸⁹Zr-Labeled Anticalin Radioligands for PET-Imaging of PSMA-Positive Tumors

et al. 2023

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Anticalin proteins directed against the prostate-specific membrane antigen (PSMA), optionally having tailored plasma half-life using PASylation technology, show promise as radioligands for PET-imaging of xenograft tumors in mice. To investigate their suitability, the short-circulating unmodified Anticalin was labeled with 68Ga (τ1/2 = 68 min), using the NODAGA chelator, whereas the half-life extended PASylated Anticalin was labeled with 89Zr (τ1/2 = 78 h), using either the linear chelator deferoxamine (Dfo) or a cyclic derivative, fusarinine C (FsC). Different PSMA targeting Anticalin versions (optionally carrying the PASylation sequence) were produced carrying a single exposed N- or C-terminal Cys residue and site-specifically conjugated with the different radiochelators via maleimide chemistry. These protein conjugates were labeled with radioisotopes having distinct physical half-lives and, subsequently, applied for PET-imaging of subcutaneous LNCaP xenograft tumors in CB17 SCID mice. Uptake of the protein tracers into tumor versus healthy tissues was assessed by segmentation of PET data as well as biodistribution analyses. PET-imaging with both the 68Ga-labeled plain Anticalin and the 89Zr-labeled PASylated Anticalin allowed clear delineation of the xenograft tumor. The radioligand A3A5.1-PAS(200)-FsC·89Zr, having an extended plasma half-life, led to a higher tumor uptake 24 h p.i. compared to the 68Ga·NODAGA-Anticalin imaged 60 min p.i. (2.5% ID/g vs 1.2% ID/g). Pronounced demetallation was observed for the 89Zr·Dfo-labeled PASylated Anticalin, which was ∼50% lower in the case of the cyclic radiochelator FsC (p < 0.0001). Adjusting the plasma half-life of Anticalin radioligands using PASylation technology is a viable approach to increase radioisotope accumulation within the tumor. Furthermore, 89Zr-ImmunoPET-imaging using the FsC radiochelator is superior to that using Dfo. Our strategy for the half-life adjustment of a tumor-targeting Anticalin to match the physical half-life of the applied radioisotope illustrates the potential of small binding proteins as an alternative to antibodies for PET-imaging.

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Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Molecular Design of ⁶⁸Ga- and ⁸⁹Zr-Labeled Anticalin Radioligands for PET-Imaging of PSMA-Positive Tumors

et al. 2023

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“…For instance, their charged groups are vulnerable to the surrounding water molecules because they can interact with them and produce hydrogen bonds, while the peptide bonds in their structure can be influenced by the proteolytic enzymes, which cause proteolytic hydrolysis. Additionally, the restricted permeability across gastrointestinal mucosa, the degradation by enzymes in the gastrointestinal tract (GIT), the reticuloendothelial system (RES) clearance, and the elimination during first-pass clearance effects are obstacles of paramount importance during either oral or parenteral administration of therapeutic proteins and peptides, thereby limiting their clinical application [7,[12][13][14][15]. Therefore, several strategies, including the coating of proteins with a protective polymeric layer or their delivery through vehicles at the nanosize scale, are being investigated in order to overcome the aforementioned limitations [16,17].…”

Section: Introductionmentioning

confidence: 99%

Polymeric Nanostructures Containing Proteins and Peptides for Pharmaceutical Applications

2022

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Over the last three decades, proteins and peptides have attracted great interest as drugs of choice for combating a broad spectrum of diseases, including diabetes mellitus, cancer, and infectious and neurological diseases. However, the delivery of therapeutic proteins to target sites should take into account the obstacles and limitations related to their intrinsic sensitivity to different environmental conditions, fragile tertiary structures, and short half-life. Polymeric nanostructures have emerged as competent vehicles for protein delivery, as they are multifunctional and can be tailored according to their peculiarities. Thus, the enhanced bioavailability and biocompatibility, the adjustable control of physicochemical features, and the colloidal stability of polymer-based nanostructures further enable either the embedding or conjugation of hydrophobic or hydrophilic bioactive molecules, which are some of the features of paramount importance that they possess and which contribute to their selection as vehicles. The present review aims to discuss the prevalent nanostructures composed of block copolymers from the viewpoint of efficient protein hospitality and administration, as well as the up-to-date scientific publications and anticipated applications of polymeric nanovehicles containing proteins and peptides.

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“…These approaches include PEG mimetics such as SAPA [ 14 ], HRM [ 15 ], GLK [ 16 ], ELP [ 17 ], XTEN [ 18 ] and PAS [ 19 ]. Similar to PEG, these PEG mimetics allow for adjusting the pharmacokinetic properties to the therapeutic need by adapting the length of the fused polypeptide chain [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

GlycoTAIL and FlexiTAIL as Half-Life Extension Modules for Recombinant Antibody Fragments

Seifert

Kontermann

2022

Molecules

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Many therapeutic proteins are small in size and are rapidly cleared from circulation. Consequently, half-life extension strategies have emerged to improve pharmacokinetic properties, including fusion or binding to long-lasting serum proteins, chemical modifications with hydrophilic polymers such as PEGylation, or, more recently, fusion to PEG mimetic polypeptides. In the present study, two different PEG mimetic approaches, the GlycoTAIL and the FlexiTAIL, were applied to increase the hydrodynamic radius of antibody fragments of different sizes and valencies, including scFv, diabody, and scFv-EHD2 fusion proteins. The GlycoTAIL and FlexiTAIL sequences of varying lengths are composed of aliphatic and hydrophilic residues, with the GlycoTAIL furthermore comprising N-glycosylation sites. All modified proteins could be produced in a mammalian expression system without reducing stability and antigen binding, and all modified proteins exhibited a prolonged half-life and increased drug disposition in mice. The strongest effects were observed for proteins comprising a FlexiTAIL of 248 residues. Thus, the GlycoTAIL and FlexiTAIL sequences represent a flexible and modular system to improve the pharmacokinetic properties of proteins.

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Challenges and advancements in the pharmacokinetic enhancement of therapeutic proteins

Cited by 19 publications

References 76 publications

Molecular Design of ⁶⁸Ga- and ⁸⁹Zr-Labeled Anticalin Radioligands for PET-Imaging of PSMA-Positive Tumors

Molecular Design of ⁶⁸Ga- and ⁸⁹Zr-Labeled Anticalin Radioligands for PET-Imaging of PSMA-Positive Tumors

Polymeric Nanostructures Containing Proteins and Peptides for Pharmaceutical Applications

GlycoTAIL and FlexiTAIL as Half-Life Extension Modules for Recombinant Antibody Fragments

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Challenges and advancements in the pharmacokinetic enhancement of therapeutic proteins

Cited by 19 publications

References 76 publications

Molecular Design of 68Ga- and 89Zr-Labeled Anticalin Radioligands for PET-Imaging of PSMA-Positive Tumors

Molecular Design of 68Ga- and 89Zr-Labeled Anticalin Radioligands for PET-Imaging of PSMA-Positive Tumors

Polymeric Nanostructures Containing Proteins and Peptides for Pharmaceutical Applications

GlycoTAIL and FlexiTAIL as Half-Life Extension Modules for Recombinant Antibody Fragments

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Product

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Molecular Design of ⁶⁸Ga- and ⁸⁹Zr-Labeled Anticalin Radioligands for PET-Imaging of PSMA-Positive Tumors

Molecular Design of ⁶⁸Ga- and ⁸⁹Zr-Labeled Anticalin Radioligands for PET-Imaging of PSMA-Positive Tumors